Agent for regeneration and/or protection of nerves

ABSTRACT

An EP2 agonist which may have an EP3 agonistic effect has an effect of regenerating and/or protecting nerves, and is therefore useful as a therapeutic agent for a disease of the peripheral nervous system, such as a lower or upper motor neuron disease, a nerve root disease, plexopathy, thoracic outlet compression syndrome, peripheral neuropathy, neurofibromatosis and neuromuscular transmission disease. An EP2 agonist which has an EP3 agonistic effect is a safe and effective agent for the regeneration and/or protection of nerves which has little influence on the circulatory system.

The present application is a Continuation of U.S. application Ser. No.11/916,374 filed Dec. 3, 2007, which is a national stage application ofPCT/JP2006/311084 filed Jun. 2, 2006, which claims the benefit ofJapanese Patent Application No. 2005-164458 filed Jun. 3, 2005, thedisclosures of which are incorporated herein in their entireties byreference.

TECHNICAL FIELD

The present invention relates to an agent for regeneration and/orprotection of nerves. More particularly, it relates to an agent forregeneration and/or protection of nerves comprising an EP2 agonist whichmay have an EP3 agonistic effect.

BACKGROUND OF THE INVENTION

The nervous system is roughly divided into central nervous system andperipheral nervous system, and the peripheral nervous systemparticularly takes charge of neurotransmission by connecting the brainand spine with somatic peripheries. The peripheral nervous system can beclassified into somatic nervous system (cerebrospinal nervous system)and autonomic nerve system. Additionally, the somatic nervous system isdivided into cranial nerves and spinal nerves. Also, when the somaticnervous system is functionally classified, those which transmit a neuralsignal (excitation) generated from a sensory receptor to the centralnerves are classified into afferent or sensory nerve fiber, while thosewhich transmit a neural signal directing from the brain and spine towardeffector organs such as muscles and glands are classified into efferentor motor nerve fiber. Cranial nerves are peripheral nerves extended fromthe brain and 12 pairs thereof are known. Some of them consist ofsensory nerve fibers; some of them consists of motor nerve fibers; andsome of them consists of mixed nerve fibers. Each of the first totwelfth nerve pairs is called olfactory nerve, optic nerve, oculomotornerve, trochlear nerve, trigeminal nerve, abducens nerve, facial nerve,auditory nerve, glossopharyngeal nerve, vagus nerve, accessory nerve andhypoglossal nerve. Among them, as nerves consisting of the sensory ormixed nerve fibers, olfactory nerve, optic nerve, trigeminal nerve,facial nerve, auditory nerve, glossopharyngeal nerve and vagus nerve areknown. The spinal nerves are peripheral nerves extended from the spineand respective 31 pairs are known. Namely, 8 pairs of cervical nerve, 12pairs of breast nerve, 5 pairs of lumbar nerve, 5 pairs of sacral nerveand a pair of coccyx nerve are known. All of the spinal nerves consistof mixed nerve fibers and contain sensory fibers (dorsal roots) extendto the skin and the like and motor fibers (ventral roots) extend toskeletal muscle.

The sensory nerve fibers, namely sensory nerves, take charge of afunction to accurately transfer stimuli such as light, sound,temperature and touch received by sensory receptors such as optic organ,auditory organ, olfactory organ, gustatory organ and the skin to thecentral nervous system. The neural signals transferred to the centralnervous system are finally transferred to each sensory area of thecerebral cortex, for example, visual area, auditory area and the like,and the sensation is normally recognized thereby. However, there is acase in which various neuropathies of these sensory nerves such as celldeath and demyelination are induced through damages of axons, myelinsheaths, Schwann cells or the like caused, for example, by viralinfection, tumor, cancer, diabetes mellitus, ischemia, injury,compression, drugs, radiotherapy and the like. As a result, sincecorrect neurotransmission is not carried out in a sensory nerve whichcaused a disorder, for example, diseases such ad hearing loss andneuropathic pain are generated. In addition to these, there is aneuropathy in which not only a specific sensory nerve but also variousperipheral nerves including sensory nerves simultaneously undergodamages caused, for example, by metabolic disease, autoimmune diseaseand the like diseases, injuries, drug intoxication and the like. In thisdisease, a single nerve, two or more nerves which present in separateregions or a large number of nerves sometimes undergo the disordersimultaneously. Its symptoms are very complex and varied, and includepain, numbness and burning sensation in a peripheral region andproprioceptive sensation reduction, hypopallesthesia, pain (includingneuropathic pain), abnormal sensation, cold, heat and the like.

Additionally, the motor unit includes anterior horn cells, efferentaxons thereof and all muscle fibers controlled by the axons. It is knownthat various peripheral nerve system diseases accompanied by motorfunction disorders including atrophy, weakness or consumption of amuscle (skeletal muscle or the like) are generated when the motor unitundergoes a certain disorder. The peripheral nerve system disease isdivided into a neurogenic disease, a myogenic disease and a mixed typedisease thereof. Examples of the neurogenic disease include diseaseswhich are generated when any region of from motor nerve cell toneuromuscular junction in motor units undergoes a disorder, and thelike. The neurogenic diseases are generated particularly when a cellbody, an axon or a neuromuscular junction of the motor unit undergoes adisorder, and their symptoms occur at peripheries of the legs and armsin most cases.

Examples of the peripheral nerve system diseases include lower and uppermotor neuron diseases (e.g., amyotrophic lateral sclerosis,paraneoplastic syndrome, progressive bulbar paralysis, progressivemuscular atrophy, primary lateral sclerosis, progressive pseudobulbarparalysis, post poliomyelitis syndrome, genetic spinal muscular atrophy(type I spinal muscular atrophy) (Werdnig-Hoffman disease), type II(intermediate) spinal muscular atrophy, type III spinal muscular atrophy(Wohlfart-Kugelberg-Welander disease), (type IV spinal muscular atrophy)and the like); nerve root diseases (e.g., hernia of intervertebral disk,spinal canal stenosis, cervical spondylosis and the like); plexusdiseases (e.g., acute brachial plexitis and the like); thoracic outletcompression syndrome; peripheral nerve disorders (e.g., mononeuropathy,multiple mononeuropathy, multiple neuropathy, Guillain-Barre syndrome,genetic neuropathy (e.g., peroneal muscular atrophy (Chalcot-Marie-Toothdisease), hypertrophic interstitial neuropathy (Dejerine-Sottasdisease), diabetic peripheral nerve disorders, neurofibromatosis (e.g.,peripheral neurofibroma (Recklinghausen disease), central nervefibromaand the like), Proteus syndrome and the like) and the like); orneuromuscular transmission diseases (e.g., myasthenia gravis, amyotoniacongenita syndrome, Eaton-Lambert syndrome, botulism, systemic tetanysyndrome, Isaacs syndrome and the like) and the like.

However, since the aforementioned peripheral nerve system diseases arediseases whose generation mechanisms are unknown or physical injuries ofnerves, so that symptomatic therapy is mainly carried out with the aimof improving the symptoms in their treatment. Clinically useful agentsapplicable to the fundamental therapy by directly acting upon the nerveswhich underwent disorders are barely known.

On the one hand, prostaglandins have been known as a metabolite in thearachidonate cascade. It has been known that the action hascyto-protective activity, uterine contractive activity, a pain-inducingeffect, a promoting effect on digestive peristalsis, an awakeningeffect, a suppressive effect on gastric acid secretion, hypotensiveactivity and diuretic activity and the like.

A recent study has proved existence of various PGE subtype receptorspossessing a different physiological or pharmacological role from eachother. At present, four receptor subtypes are known and they are calledEP1, EP2, EP3, and EP4 (Negishi M., et al., J. Lipid Mediators CellSignaling, 12, 379-391 (1995)).

It is described that a prostaglandin-like compound described inEP860430A1 has an EP2 agonistic effect and is useful for a preventionand/or a treatment of immune diseases, asthma, abnormal boneformulation, neuron cell death, liver damage, premature birth, abortionor retinal neuropathy such as glaucoma etc (Patent Reference 1).

It is described that a prostaglandin-like compound described inWO98/34916 has an EP3 agonistic effect and is useful for a preventionand/or a treatment of liver diseases, kidney diseases, pancreatitis ormyocardial infarction etc (Patent Reference 2).

It is described that a prostaglandin-like compound described inWO03/074483 has an EP2 agonistic effect and is useful for a preventionand/or a treatment of immune diseases, allergic diseases, neuronal celldeath, dysmenorrhea, premature birth, abortion, baldness, retinalneuropathy, erectile dysfunction, arthritis, pulmonary injury, pulmonaryfibrosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonarydisease, hepatic injury, acute hepatitis, liver cirrhosis, shock,nephritis, renal failure, circulatory diseases, systemic inflammatoryresponse syndrome, sepsis, hemophagocytosis syndrome, macrophageactivation syndrome, still disease, Kawasaki disease, burn, systemicgranuloma, ulcerative colitis, Crohn disease, hypercytokinemia atdialysis, multiple organ failure, or bone diseases etc (Patent Reference3).

It is described in WO04/089411 that the combination of the compoundwhich has an EP2 agonistic effect and the compound which has EP3agonistic effect is useful for spinal canal stenosis (Patent Reference4).

It is described in WO05/053707 that the prostaglandin-like compound isuseful as the agent for increasing cauda equina blood flow (PatentReference 5).

On the one hand, it is known that EP2 receptor, which is the subtype ofPGE₂ receptor, relates to the protecting effect of nerves in cerebra(Non-Patent Referent 1).

However, it is neither indicated nor described that an EP2 agonist whichmay have an EP3 agonistic effect has the regenerating or the protectingeffect of peripheral nerves.

[Patent Reference 1] EP860430A1

[Patent Reference 2] WO98/34916

[Patent Reference 3] WO03/074483

[Patent Reference 4] WO04/089411

[Patent Reference 5] WO05/053707

[Non-Patent Referent 1] Nurobiology of Disease, 24, 1, 257-268 (2004)

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

Great concern has been directed toward a highly safe and effective nerveregenerative and/or protective agent which directly acts on disorderednerves in peripheral nerve system diseases.

Means for Solving the Problems

The present inventors studied eagerly, and as a result, found that anEP2 agonist which may have an EP3 agonistic effect has the regeneratingand the protecting effect of nerves. Furthermore, the present inventorsfound that the EP2 agonist which may have the EP3 agonistic effect haslittle influence on the blood pressure and the ventricular rate and thelike, a little influence on the circulatory system and can be a highsafe and effective agent for the prevention and/or treatment of adisease of the peripheral nervous system, and completed the presentinvention.

That is to say, the present invention relates to:1. an agent for regeneration and/or protection of nerves comprising anEP2 agonist which may have an EP3 agonistic effect;2. the agent for the regeneration and/or protection of nerves describedin the above 1, comprising an EP2 agonist having an EP3 agonisticeffect;3. the agent described in the above 2, wherein the EP2 agonist having anEP3 agonistic effect is a compound represented by formula (I):

wherein ring A is a 5 or 6-membered ring which may comprise 1 to 3hetero atom(s) selected from nitrogen, oxygen and sulfur in addition toX and Y, and furthermore may have a substituent(s),

X and Y are each independently nitrogen or carbon,

D is hydrocarbon which may have a substituent(s),

E is a bond, oxygen or optionally oxidized sulfur,

G is a bond, hydrocarbon which may have a substituent(s) or hetero ringwhich may have a substituent(s),

J is an acidic group which may be protected,

W is hydrocarbon which may have a substituent(s), a salt thereof, anN-oxide thereof, an S-oxide thereof, a solvate thereof or a prodrugthereof, or a cyclodextrin clathrate thereof;

4. the agent described in the above 3, wherein the compound representedby formula (I) is a compound represented by formula (I-1):

wherein ring A¹ is 5 or 6 membered ring which may comprise 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur in addition to X andY, and may have more substituent(s),

E¹ is oxygen or optionally oxidized sulfur,

R is hydrogen or C1-8 aliphatic hydrocarbon, and the other symbols havethe same meanings as those described in the above 3;

5. the agent described in the above 4 wherein the compound representedby formula (I-1) is a compound represented by formula (I-5):

wherein R¹ is hydrogen or C1-4 aliphatic hydrocarbon group, R² ishydrocarbon group which may have a substituent(s),

is β-configuration, and the other symbols have the same meanings asthose described in the above 4;6. a medicament combined an EP2 agonist having an EP3 agonistic effect,with one or more selected from an EP2 agonist and an EP3 agonist;7. the agent described in the above 1, wherein the regeneration and/orprotection of nerves is a prevention and/or a treatment for a disease ofthe peripheral nervous system;8. a medicament comprising an EP2 agonist which may have an EP3agonistic effect, and one or more species selected from prostaglandins,prostaglandin derivatives, nonsteroidal anti-inflammatory drugs,vitamins, muscle relaxants, antidepressants, nitric oxide synthaseinhibitors, aldose reductase inhibitors, poly ADP-ribose polymeraseinhibitors, excitatory amino acid receptor antagonists, radicalscavengers, astrocyte modulators, phosphodiesterase inhibitor andimmunosuppressive agent in combination;9. a method for the regeneration and/or protection of nerves, whichcomprises administering to a mammal an effective amount of an EP2agonist which may have an EP3 agonistic effect;10. a use of an EP2 agonist which may have an EP3 agonistic effect, forthe manufacture of an agent for regeneration and/or protection ofnerves;11. a compound represented by formula (I-2):

wherein ring A² is a 5 or 6-membered ring which may comprise 1 to 3hetero atom(s) selected from nitrogen, oxygen and sulfur, and may havemore substituent(s), and

the other symbols have the same meanings as those described in the above4, excluding

-   2-[(2-{(1R,2R)-2-[(1E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylic    acid,-   2-[(2-{(1R,2R)-2-[(1E,3R)-3-hydroxy-4,4-dimethyl-1-octenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylic    acid,-   2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1-nonenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylic    acid,-   2-[(2-{(1R,2R)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylic    acid and-   2-[(2-{(1R,2R)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxocyclopentyl}ethyl)sulfonyl]-1,3-thiazole-4-carboxylic    acid,

a salt thereof, an N-oxide thereof, an S-oxide thereof, a solvatethereof or a prodrug thereof, or a cyclodextrin clathrate thereof;

12. the compound described in the above 11, which is represented byformula (I-3):

wherein

is α-configuration, and the other symbols have the same meanings asthose described in the above 4 and above 5;13. the compound described in the above 12, wherein R¹ is hydrogen orC1-4 alkyl group, R² is C1-8 aliphatic hydrocarbon group which may havea substituent(s), or (C3-8 cycloalkyl)-(C1-4 aliphatic hydrocarbon)group which may have a substituent(s),14. the compound described in the above 11, which is selected from

-   2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclohexyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound17),-   2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,8-dimethyl-1,7-nonadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound18-5),-   2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound18-6),-   2-[(2-{(1R,2R)-2-[(1E,4S)-    -4-hydroxy-4-methyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound17-1),-   2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1,7-octadien-1-yl]-5-oxo    cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid (compound32),-   2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4,8-dimethyl-1-nonen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound25-2a),-   2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound25-3a),-   2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclobutyl-4-hydroxy-4-methyl-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound25-4a),-   2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound25-5a),-   2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-7-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound31a) and-   2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclobutyl-4-hydroxy-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound3′-1);-   15.    2-[(2-{(2R)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound24-1),-   2-[(2-{(2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound24-2),-   2-[(2-{(2R)-2-[(1E)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound24-3),-   2-[(2-{(2R)-2-[(1E,4R)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound34),-   2-[(2-{(2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound34-1) or-   2-[(2-{(2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic    acid (compound34-2),

a salt thereof, an N-oxide thereof, an S-oxide thereof, a solvatethereof or a prodrug thereof, or a cyclodextrin clathrate thereof;

16. an agent for the regeneration and/or protection of nerves, or anagent to increase cauda equina blood flow comprising the compound whichis represented by formula (I-2) or the compound described in the above15, the salt thereof, the N-oxide thereof, the S-oxide thereof, thesolvate thereof or the prodrug thereof, or the cyclodextrin clathratethereof;17. the agent described in the above 16, which is a preventive and/or atherapeutic agent for spinal canal stenosis and/or cervical vertebrasymptom.

The “5 or 6 membered ring” represented by ring A may comprise 1 to 3hetero atom(s) selected from nitrogen, oxygen and sulfur in addition toX and Y. The “5 or 6 membered ring” represented by ring A is, forexample, “5 or 6 membered mono-carbocyclic ring” or “5 or 6 memberedmono-heterocyclic ring” and the like. The “5 or 6 memberedmono-carbocyclic ring” includes, for example, cyclopentane, cyclohexane,cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene or benzeneand the like. The “5 or 6 membered mono-heterocyclic ring”, which is a 5or 6 membered mono-heterocyclic ring comprising 1 to 5 hetero atom(s)selected from nitrogen, oxygen and sulfur, includes, for example,pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, triazine, furan, thiophene, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, thiadiazole, pyran,thiopyran, oxazine, oxadiazine, thiazine, thiadiazine, pyrroline,imidazoline, triazoline, tetrazoline, pyrazoline, dihydropyridine,tetrahydropyridine, dihydropyrazine, tetrahydropyrazine,dihydropyrimidine, tetrahydropyrimidine, dihydropyridazine,tetrahydropyridazine, tetrahydrotriazine, dihydrofuran, dihydropyran,dihydrothiophene, dihydrothiopyran, dihydrooxazole, dihydroisoxazole,dihydrothiazole, dihydroisothiazole, dihydrofurazan, dihydrooxadiazole,dihydrooxazine, dihydrooxadiazine, dihydrothiadiazole, dihydrothiazine,dihydrothiadiazine, pyrrolidine, imidazolidine, triazolidine,tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine,perhydropyridazine, tetrahydrofuran, tetrahydropyran, perhydrooxepine,tetrahydrothiophene, tetrahydrothiopyran, tetrahydrooxazole(oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole(thiazolidine), tetrahydroisothiazole (isothiazolidine),tetrahydrofurazan, tetrahydrooxadiazole (oxadiazolidine),tetrahydrooxazine, tetrahydrooxadiazine, tetrahydrothiadiazole(thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine,morpholine, thiomorpholine or oxathiane and the like. A 5 or 6 memberedbridged bi-heterocyclic ring such as (1R,5S)-3-azabicyclo[3.1.0]hexanering is also included in “5 or 6 membered ring”.

The ring A is preferably, cyclopentane, cyclopentene, pyrrolidine,imidazolidine, tetrahydrooxazole, tetrahydrothiazole or(1R,5S)-3-azabicyclo[3.1.0]hexane ring and the like, more preferablycyclopentane or pyrrolidine and the like.

The ring A may have an optional substituent(s). 1 to 5 substituent(s),preferably 1 to 3 one(s), may be substituted at replaceable positions.When the number of substituents is two or more, each substituent may bethe same or different. When the number of substituents of ring A is twoor more, for example, two substituents of ring A taken together withatom on ring A may form a ring. The formed ring includes C3-7cycloalkane (such as cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane etc).

The substituent of the ring A includes, for example, (1) hydrocarbongroup which may have a substituent(s), (2) heterocyclic group which mayhave a substituent(s), (3) amino which may have a protecting group(s),(4) C1-4 alkylsulfonyl such as methylsulfonyl and ethylsulfonyl etc, (5)phenylsulfonyl, (6) halogen atom such as fluorine, chlorine, bromine andiodine, (7) carboxyl, (8) cyano, (9) nitro, (10) oxo, (11) thioxo, (12)hydroxy which may have a protecting group(s), (13) mercapto which mayhave a protecting group(s), (14) carbamoyl which may have asubstituent(s), (15) sulfamoyl which may have a substituent(s), (16)alkoxycarbonyl (e.g., C1-6 alkoxycarbonyl such as methoxycarbonyl,ethoxycarbonyl and tert-butoxycarbonyl etc), (17) sulfo (—SO₃H), (18)sulfino, (19) phosphono, (20) amidino, (21) imino, (22) —B(OH)₂ or (23)C1-6 acyl such as formyl, acetyl, propionyl and butylyl and the like.

The “hydrocarbon group” in the “(1) hydrocarbon group which may have asubstituent(s)” as the substituent of the ring A includes, for example,a straight or a branched aliphatic hydrocarbon group; cyclic hydrocarbongroup; C7-16 alalkyl such as benzyl and phenylethyl; (C3-8cycloalkyl)-(C1-8 aliphatic hydrocarbon) group such as cyclohexylmethyl,cyclohexylethyl, cyclohexylpropyl, 1-methyl-1-cyclohexylmethyl,cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylpropenyl,cyclobutylbutenyl, cyclopentylmethyl, cyclopentylethyl,cyclopentylpropyl, cyclopentylpropenyl, cyclopropylmethyl andcyclopropylethyl and the like.

The “straight or branched aliphatic hydrocarbon group” includes, forexample, “C1-12 aliphatic hydrocarbon group”. The “C1-12 aliphatichydrocarbon group” includes, for example, C1-12 alkyl such as methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, undecyl and dodecyl etc; C2-12 alkenyl suchas vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl, undecenyl, dodecenyl, butadienyl, pentadienyl,hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl,undecadienyl, dodecadienyl, hexatrienyl, heptatrienyl, octatrienyl,nonatrienyl, decatrienyl, undecatrienyl and dodecatrienyl etc; C2-12alkynyl such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl,octynyl, nonynyl, decynyl, undecynyl, dodecynyl, butadiynyl,pentadiynyl, hexadiynyl, heptadiynyl, octadiynyl, nonadiynyl,decadiynyl, undecadiynyl, dodecadiynyl, hexatriynyl, heptatriynyl,octatriynyl, nonatriynyl, decatriynyl, undecatriynyl or dodecatriynyland the like.

The “cyclic hydrocarbon” in the “cyclic hydrocarbon group” includes“saturated cyclic hydrocarbon” or “unsaturated cyclic hydrocarbon” andthe like. The “saturated cyclic hydrocarbon” includes, for example,“3-15 membered saturated cyclic hydrocarbon”. The “3-15 memberedsaturated cyclic hydrocarbon” includes, for example, 3-15 memberedcycloalkane such as cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane,cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane andcyclopentadecane etc; or 3-15 membered saturated polycyclic hydrocarbonsuch as perhydropentalene, perhydroazulene, perhydroindene,perhydronaphthalene, perhydroheptalene, spiro[4.4]nonane,spiro[4.5]decane, spiro[5.5]undecane, bicyclo[2.2.1]heptane,bicyclo[3.1.1]heptane, bicyclo[2.2.2]octane, adamantane or noradamantaneand the like.

The “unsaturated cyclic hydrocarbon” includes, for example, “3-15membered unsaturated cyclic hydrocarbon”. The “3-15 membered unsaturatedcyclic hydrocarbon” includes, for example, 3-8 membered cycloalkene suchas cyclopentene, cyclohexene, cycloheptene, cyclooctene,cyclopentadiene, cyclohexadiene, cycloheptadiene and cyclooctadiene etc;3-15 membered aromatic hydrocarbon such as benzene, azulene,naphthalene, phenanthrene and anthracene etc; 3-15 membered unsaturatedpolycyclic hydrocarbon such as pentalene, indene, indane,dihydronaphthalene, teterahydronaphthalene, heptalene, biphenylene,as-indacene, s-indacene, acenaphthene, acenaphthylene, fluorene,phenalene, bicyclo[2.2.1]hept-2-ene, bicyclo[3.1.1]hept-2-ene orbicyclo[2.2.2]oct-2-ene and the like.

The “substitutent” in the “hydrocarbon group which may have asubstituent(s)” as the substituent of the ring A includes, for example,(1) hydrocarbon group (here, this “hydrocarbon group” has the samemeaning as the “hydrocarbon group” in the “(1) hydrocarbon group whichmay have a substituent(s)” as the substituent of the ring A describedabove) which may have a substituent(s) (e.g., amino, sulfo, halogenatom, carboxy, cyano, nitro, oxo, thioxo, hydroxy, C1-8 alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, cyclohexylmethyloxy, benzyloxy etc), trifluoromethyl,trifluoromethoxy etc), (2) heterocyclic ring (here this “heterocyclicring” has the same meaning as the “heterocyclic ring” in the “(2)heterocyclic ring which may have a substituent(s)” as the substituent ofthe ring A described below) which may have a substituent(s) (e.g.,hydrocarbon group (here, this “hydrocarbon group” has the same meaningas the “hydrocarbon group” in the “(1) hydrocarbon group which may havea substituent(s)” as the substituent of the ring A described above),amino, sulfo, halogen atom, carboxy, cyano, nitro, oxo, thioxo, hydroxy,methoxy, trifluoromethyl, trifluoromethoxy, acetyl etc), (3) amino, (4)C1-6 acylamino such as acetylamino and propionylamino and the like, (5)primary or secondary amino substituted by hydrocarbon group such asmethylamino, ethylamino, propylamino, isopropylamino, butylamino,dimethylamino, diethylamino, cyclohexylamino,1-carbamoyl-2-cyclohexylethylamino, N-butyl-N-cyclohexylmethylamino,phenylamino and butoxyphenylamino (this “hydrocarbon group” has the samemeaning as the “hydrocarbon group” in “(1) hydrocarbon group which mayhave a substituent(s)” as the substituent of the ring A described aboveand may be substituted by C1-4 alkoxy (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy etc), oxo, amino,carbamoyl etc), (6) C1-4 alkylsulfonylamino such as methylsulfonylaminoand ethylsulfonylamino and the like, (7) phenylsulfonylamino, (8) C1-4alkylsulfonyl such as methylsulfonyl and ethylsulfonyl and the like, (9)phenylsulfonyl, (10) halogen atom (fluorine, chlorine, bromine, iodine),(11) carboxy, (12) cyano, (13) nitro, (14) oxo, (15) thioxo, (16)hydroxy, (17) C1-8 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclohexylmethyloxy orbenzyloxy (here, the alkoxy may be substituted by halogen atom etc),(18) C3-8 cycloalkyloxy such as cyclohexyloxy (the C3-8 cycloalkyloxymay be substituted by halogen atom etc), (19) phenoxy which may besubstituted by methyl and halogen atom and the like, (20) mercapto, (21)C1-4 alkylthio such as methylthio, ethylthio, propylthio, isopropylthio,butylthio and tert-butylthio and the like, (22) phenylthio, (23)carbamoyl, (24) aminocarbonyl substituted by hydrocarbon group such asN-butylaminocarbonyl, N-cyclohexylmethylaminocarbonyl,N-butyl-N-cyclohexylmethylaminocarbonyl, N-cyclohexylaminocarbonyl andphenylaminocarbonyl (this “hydrocarbon group” has a same meaning as the“hydrocarbon group” in the “(1) hydrocarbon group which may have asubstituent(s)” as the substituent of the ring A described above), (25)sulfamoyl, (26) aminosulfonyl substituted by hydrocarbon group such asmethylaminosulfonyl (this “hydrocarbon group” has a same meaning as the“hydrocarbon group” in the “(1) hydrocarbon group which may have asubstituent(s)” as the substituent of the ring A described above), (27)aminosulfonyl which is substituted by the hydrocarbon group substitutedby amino such as dimethylaminoethylaminosulfonyl anddimethylaminopropylaminosulfonyl (here, this “hydrocarbon group” has asame meaning as the “hydrocarbon group” in the “(1) hydrocarbon groupwhich may have a substituent(s)” as the substituent of the ring Adescribed above), (28) C1-6 alkoxycarbonyl such as methoxycarbonyl,ethoxycarbonyl and tert-butoxycarbonyl and the like, (29) sulfo (—SO₃H),(30) sulfino, (31) phosphono, (32) amidino, (33) imino, (34) —B(OH)₂,(35) C1-4 alkylsulfinyl such as methylsulfinyl and ethylsulfinyl and thelike, (36) C1-6 acyl such as formyl, acetyl, propionyl and butylyl andthe like, (37) benzoyl, (38) hydroxyimino, or (39) alkyloxyimino such asmethyloxyimino and ethyloxyimino and the like. The “hydrocarbon groupwhich may have a substituent(s)” may have 1 to 5 substituent(s) selectedfrom (1) to (39) described above. When the number of substituents is twoor more, each substituent may be the same or different. Moreover, forexample, two substituents taken together with carbon on hydrocarbongroup may form a ring.

The “heterocyclic ring” in “(2) heterocyclic ring which may have asubstituent(s)” as the substituent of the ring A includes, for example,mono-, bi- or tri-heterocyclic ring which may be comprising 1 to 7hetero atom(s) selected from nitrogen, oxygen and sulfur. The“heterocyclic ring” includes, for example, the “3-15 memberedunsaturated mono-, bi- or tri-heterocyclic ring”, the “3-15 memberedsaturated mono-, bi- or tri-heterocyclic ring” and the like.

The “3-15 membered unsaturated mono-, bi- or tri-heterocyclic ring”includes, for example, aromatic mono-heterocyclic ring such as pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, triazine, furan, thiophene, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole and thiadiazole and the like,aromatic fused heterocyclic ring such as indole, isoindole, benzofuran,isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline,isoquinoline, purine, phthalazine, pteridine, naphthyridine,quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole,benzimidazole, benzofurazan, benzothiadiazole, benztriazole, carbazole,β-carboline, acridine, phenazine, dibenzofuran, dibenzothiophene,phenanthridine, phenanthroline or perimidine and the like, non-aromaticunsaturated heterocyclic ring such as azepine, diazepine, pyran,oxepine, thiopyran, thiepine, oxazine, oxadiazine, oxazepine,oxadiazepine, thiazine, thiadiazine, thiazepine, thiadiazepine,indolizine, dithianaphthalene, quinolizine, chromene, benzoxepine,benzoxazepine, benzoxadiazepine, benzothiepine, benzothiazepin,benzothiadiazepine, benzoazepine, benzodiazepine, xanthene,phenothiazine, phenoxazine, phenoxathiin, thianthrene, pyrroline,imidazoline, triazoline, tetrazoline, pyrazoline, dihydropyridine,tetrahydropyridine, dihydropyrazine, tetrahydropyrazine,dihydropyrimidine, tetrahydropyrimidine, dihydropyridazine,tetrahydropyridazine, tetrahydrotriazine, dihydroazepine,tetrahydroazepine, dihydrodiazepine, tetrahydrodiazepine, dihydrofuran,dihydropyran, dihydrooxepine, tetrahydrooxepine, dihydrothiophene,dihydrothiopyran, dihydrothiepine, tetrahydrothiepine, dihydrooxazole,dihydroisoxazole, dihydrothiazole, dihydroisothiazole, dihydrofurazan,dihydrooxadiazole, dihydrooxazine, dihydrooxadiazine, dihydrooxazepine,tetrahydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,dihydrothiadiazole, dihydrothiazine, dihydrothiadiazine,dihydrothiazepine, tetrahydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, indoline, isoindoline, dihydrobenzofuran,dihydroisobenzofuran, dihydrobenzothiophene, dihydroisobenzothiophene,dihydroindazole, dihydroquinoline, tetrahydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,benzoxathiane, dihydrobenzooxazine, dihydrobenzothiazine,pyrazinomorpholine, dihydrobenzooxazole, dihydrobenzothiazole, dihydrobenzimidazole, dihydrobenzoazepine, tetrahydrobenzoazepine,dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane,dihydrobenzoxazepine, tetrahydrobenzoxazepine, dihydrocarbazole,tetrahydrocarbozole, dihydro-β-carboline, tetrahydro-β-carboline,dihydroacridine, tetrahydroacridine, dihydrodibenzofuran,dihydrodibenzothiophene, tetrahydro dibenzofuran,tetrahydrodibenzothiophene, dioxaindane, benzodioxane, chromane,benzodithiolane, benzodithiane,6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine,2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole or6,7,8,9-tetrahydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine and thelike. Moreover, the “3-15 membered saturated mono-, bi- ortri-heterocyclic ring” includes, for example, aziridine, azetidine,pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine,piperidine, piperazine, perhydropyrimidine, perhydropyridazine,perhydroazepine, perhydrodiazepine, perhydroazocine, oxirane, oxetane,tetrahydrofuran, tetrahydropyran, perhydrooxepine, thiirane, thietane,tetrahydrothiophene, tetrahydrothiopyran, perhydrothiepine,tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isooxazolidine),tetrahydrothiazole (thiazolidine), tetrahydroisothiazole(isothiazolidine), tetrahydrofurazan, tetrahydrooxadiazole(oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine,perhydrooxazepine, perhydrooxadiazepine, tetrahydrothiadiazole(thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine,perhydrothiazepine, perhydrothiadiazepine, morpholine, thiomorpholine,oxathiane, perhydrobenzofuran, perhydroisobenzofuran,perhydrobenzothiophene, perhydroisobenzothiophene, perhydroindazole,perhydroquinoline, perhydroisoquinoline, perhydrophthalazine,perhydronaphthyridine, perhydroquinoxaline, perhydroquinazoline,perhydrocinnoline, perhydrobenzooxazole, perhydrobenzothiazole,perhydrobenzimidazole, perhydrocarbazole, perhydro-β-carboline,perhydroacridine, perhydrodibenzofuran, perhydrodibenzothiophene,dioxolane, dioxane, dithiolane or dithiane and the like.

The “substituent” in the “(2) heterocyclic ring which may have asubstituent(s)” as the substituent of the ring A includes, for example,hydrocarbon group (This “hydrocarbon group” has a same meaning as the“hydrocarbon group” in the “(1) hydrocarbon group which may have asubstituent(s)” as the substituent of the ring A described above),amino, sulfo, halogen atom, carboxyl, cyano, nitro, oxo, thioxo,hydroxyl, methoxy, trifluoromethyl, trifluoromethoxy or acetyl group andthe like. The “(2) heterocyclic ring which may have a substituent(s)”may have 1 to 5 substituent(s) selected from the “substituent” describedabove. When the number of substituents is two or more, each substituentmay be the same or different.

The “protecting group” in the “(3) amino group which may have aprotecting group(s)” as the substituent of the ring A includes, forexample, hydrocarbon group, sulfo group or sulfonyl group binding withhydrocarbon group which may have a substituent(s) and the like. Here the“hydrocarbon group which may have a substituent(s)” has a same meaningas the “(1) hydrocarbon group which may have a substituent(s)” as thesubstituent of the ring A described above. The “(3) amino group whichmay have a protecting group(s)” may have 1 or 2 protecting group(s)selected from the “protecting group” described above. When the number ofprotecting groups is two, each protecting group may be the same ordifferent.

The “protecting group” in the “(12) hydroxyl group which may have aprotecting group(s)” or the “(13) mercapto group which may have aprotecting group(s)” as the substituent of the ring A includes, forexample, hydrocarbon group which may have a substituent(s) and the like.Here the “hydrocarbon group which may have a substituent(s)” has a samemeaning as the “(1) hydrocarbon group which may have a substituent(s)”as the substituent of the ring A described above.

The “substituent” in the “(14) carbamoyl group which may have asubstituent(s)” or the “(15) sulfamoyl group which may have asubstituent(s)” as the substituent of the ring A includes, for example,hydrocarbon group which may have a substituent(s) and the like. Here the“hydrocarbon group which may have a substituent(s)” has a same meaningas the “(1) hydrocarbon group which may have a substituent(s)” as thesubstituent of the ring A described above.

The substituent of the ring A includes preferably C1-4 alkyl group suchas methyl, ethyl, propyl and butyl, oxo, hydroxyl or halogen atom.

The “5 or 6 membered ring” represented by a ring A¹ may comprise 1 to 3hetero atom(s) selected from nitrogen, oxygen and sulfur in addition toX and Y.

The “5 or 6 membered ring” represented by the ring A¹ includes, forexample, “5 or 6 membered mono-carbocyclic ring” or “5 or 6mono-heterocyclic ring” and the like. The “5 or 6 memberedmono-carbocyclic ring” includes, for example, cyclopentane, cyclohexane,cyclopentene, cyclohexene, cyclopentadiene or cyclohexadiene and thelike. The “5 or 6 mono-heterocyclic ring” includes, for example,pyrroline, imidazoline, triazoline, tetrazoline, pyrazoline,tetrahydropyridine, tetrahydropyrazine, tetrahydropyrimidine,tetrahydropyridazine, tetrahydrotriazine, dihydrofuran, dihydropyran,dihydrothiophene, dihydrothiopyran, dihydroisoxazole,dihydroisothiazole, dihydrooxazine, dihydrooxadiazine, dihydrothiazine,dihydrothiadiazine, pyrrolidine, imidazolidine, triazolidine,tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine,perhydropyridazine, tetrahydrofuran, tetrahydropyran, perhydrooxepine,tetrahydrothiophene, tetrahydrothiopyran, tetrahydrooxazole(oxazolidine), tetrahydroisoxazole (isooxazolidine), tetrahydrothiazole(thiazolidine), tetrahydroisothiazole (isothiazolidine),tetrahydrofurazan, tetrahydrooxadiazole (oxadiazolidine),tetrahydrooxazine, tetrahydrooxadiazine, tetrahydrothiadiazole(thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine,morpholine, thiomorpholine or oxathiane and the like. Moreover, a 5 or 6membered bridged bi-heterocyclic ring such as(1R,5S)-3-azabicyclo[3.1.0]hexane is also included in “5 or 6 memberedring”.

Moreover, the ring A¹ may have 1 to 3 optional substituent(s) inaddition to a substituent (e.g., oxo) represented by formula (I-1). Thisoptional substituent may be substituted at the replaceable positions ofthe ring A¹. When the number of substituents is two or more, eachsubstituent may be the same or different. Moreover, when the number ofsubstituents in the ring A¹ is two or more, for example, twosubstituents of ring A¹ taken together with atom on the ring A¹ may forma ring. The formed ring includes, for example, C3-7 cycloalkyl group(e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) andthe like. The substituent of the ring A¹ includes, for example, thesubstituent described as the substituent of the ring A described above.

The ring A¹ is preferably, for example, cyclopentane, cyclopentene,pyrrolidine, imidazolidine, tetrahydrooxazole, tetrahydrothiazole or(1R,5S)-3-azabicyclo[3.1.0]hexane etc, more preferably, cyclopentane orpyrrolidine and the like.

The substituent aside from the substituent represented by formula (I-1)of the ring A¹ is preferably C1-4 alkyl group such as methyl, ethyl,propyl and butyl, hydroxyl or halogen atom.

The “5 or 6 membered ring” represented by ring A² may comprise 1 to 3hetero atom(s) selected from nitrogen, oxygen and sulfur.

The “5 or 6 membered ring” represented by ring A² includes, for example,“5 or 6 membered mono-carbocyclic ring” or “5 or 6 mono-heterocyclicring” and the like. The “5 or 6 membered mono-carbocyclic ring”includes, for example, cyclopentane, cyclohexane, cyclopentene,cyclohexene, cyclopentadiene or cyclohexadiene and the like. The “5 or 6mono-heterocyclic ring” includes, for example, pyran, thiopyran,oxazine, thiazine, pyrroline, pyrazoline, dihydropyridine,tetrahydropyridine, dihydropyrimidine, tetrahydropyrimidine,dihydropyridazine, tetrahydropyridazine, tetrahydrotriazine,dihydrofuran, dihydropyran, dihydrothiophene, dihydrothiopyran,dihydroisoxazole, dihydroisothiazole, dihydrooxazine, dihydrothiazine,pyrrolidine, pyrazolidine, piperidine, perhydropyrimidine,perhydropyridazine, tetrahydrofuran, tetrahydropyran,tetrahydrothiophene, tetrahydrothiopyran, tetrahydroisoxazole(isooxazolidine), tetrahydroisothiazole (isothiazolidine),tetrahydrooxazine or tetrahydrothiazine and the like.

Moreover, the ring A² may have 1 to 3 optional substituent(s) inaddition to a substituent (e.g., oxo) represented by formula (I-2). Thisoptional substituent may be substituted at the replaceable positions ofthe ring A². When the number of substituents is two or more, eachsubstituent may be the same or different. Moreover, when the number ofsubstituents of the ring A² is two or more, for example, twosubstituents of ring A² taken together with atom on the ring A² may forma ring. The formed ring includes, for example, C3-7 cycloalkyl group(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl)and the like. The substituent aside from the substituent represented byformula (I-2) of the ring A² includes, for example, the substituentdescribed as the substituent of the ring A described above.

The ring A² is preferably, for example, cyclopentane or cyclopentene.

The substituent aside from the substituent represented by formula (I-2)of the ring A² is preferably C1-4 alkyl group such as methyl, ethyl,propyl and butyl, hydroxyl or halogen atom.

The “hydrocarbon group” in the “hydrocarbon group which may have asubstituent(s)” represented by D and G includes, for example, a divalentstraight or branched aliphatic hydrocarbon group and the like. The“divalent straight or branched aliphatic hydrocarbon group” includes,for example, “C1-8 divalent aliphatic hydrocarbon group” and the like.The “C1-8 divalent aliphatic hydrocarbon group” includes, for example,C1-8 alkylene such as methylene, ethylene, propylene, isopropylene,butylene, sec-butylene, tert-butylene, pentylene, hexylene, heptylene oroctylene, C2-8 alkenylene such as vinylene, propenylene, butenylene,pentenylene, hexenylene, heptenylene, octenylene, butadienylene,pentadienylene, hexadienylene, heptadienylene, ocatadienylene,hexatrienylene, heptatrienylene or octatrienylene, C2-8 alkynylene suchas ethynylene, propynylene, butynylene, pentynylene, hexynylene,heptynylene, octynylene, butadiynylene, pentadiynylene, hexadiynylene,heptadiynylene, octadiynylene, hexatriynylene, heptatriynylene oroctatriynylene and the like. This “hydrocarbon group” may substituted bythe “substituent” in the “(1) hydrocarbon group which may have asubstituent(s)” as the substituent of the ring A described above.

D is preferably, for example, C1-6 alkylene or C2-6 alkenylene and thelike.

The “heterocyclic ring which may have a substituent(s)” represented by Ghas a same meaning as the “(2) heterocyclic ring which may have asubstituent(s)” as the substituent of the ring A described above. The“heterocyclic ring which may have a substituent(s)” represented by Gincludes preferably, for example, 5 or 6 membered mono-heterocyclic ring(This “5 or 6 membered mono-heterocyclic ring” has a same meaning as the“5 or 6 membered mono-heterocyclic ring” in the ring A described above),and more preferably,

(wherein the arrow is a binding part of E to J) and the like.

The “optionally oxidized sulfur” represented by E, E¹ and E² includes,for example, —S—, —SO— or —SO₂—.

E, E¹ and E² are preferably optionally oxidied sulfur, and are morepreferably —S— or —SO₂—.

The “acidic group” in the “acidic group which may be protected”represented by J means the “acidic group” which may be protected by a“protecting group”. Examples of the “acidic group” include carboxy(—COOH), sulfo (—SO₃H), sulfino (—SO₂H) and sulfonamide (—SO₂NH₂ or—NR¹⁰¹SO₃H(R¹⁰¹ is hydrogen or hydrocarbon group which may have asubstituent(s). Here the “hydrocarbon group which may have asubstituent(s)” represents the “(1) hydrocarbon group which may have asubstituent(s)” as the substituent of the ring A described above.)),phosphono (—PO(OH)₂), phenol (—C₆H₄OH) or the various types of Brønstedacid such as a nitrogen-containing ring residue having hydrogen fromwhich can be removed as proton. The “Brønsted acid” means a substancewhich gives hydrogen ion to other substance. Examples of the“nitrogen-containing ring residue having hydrogen from which can beremoved as proton” include

An “acidic group” is preferably, for example, carboxy and the like.

Moreover, the “protecting group” includes hydrocarbon group which mayhave a substituent(s), amino group which may have a protecting group(s),hydroxyl group which may have a protecting group(s) and the like. Here,the “hydrocarbon group which may have a substituent(s)”, the “aminogroup which may have a protecting group(s)” and the “hydroxyl groupwhich may have a protecting group(s)” have same meanings as the “(1)hydrocarbon group which may have a substituent(s)”, the “(3) amino groupwhich may have a protecting group(s)” and the “(12) hydroxyl group whichmay have a protecting group(s)” as the substituent of the ring Adescribed above respectively. The “protecting group” includes preferablythe “hydrocarbon group which may have a substituent(s)”, andspecifically, for example, methyl, ethyl, propyl, isopropyl, butyl ortert-butyl and the like.

J includes preferably, for example, carboxy group which may have aprotecting group(s), more preferably —COOR (wherein R representshydrogen or C1-8 aliphatic hydrocarbon group) and more preferably —COOH.

The “C1-8 aliphatic hydrocarbon group” represented by R includes C1-8alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, pentyl, hexyl, heptyl or octyl group and the like, C2-8alkenyl group such as vinyl, propenyl, butenyl, pentenyl, hexenyl,heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl,octadienyl, hexatrienyl, heptatrienyl or octatrienyl and the like, C2-8alkynyl group such as ethynyl, propynyl, butynyl, pentynyl, hexynyl,heptynyl, octyny, butadiynyl, pentadiynyl, hexadiynyl, heptadiynyl,octadiynyl, hexatriynyl, heptatriynyl or octatriynyl and the like.

The “hydrocarbon group which may have a substituent(s)” represented by Whas a same meaning as the “(1) hydrocarbon group which may have asubstituent(s)” as the substituent of the ring A described above.

W is preferably, for example,

wherein R¹ is hydrogen or C1-4 aliphatic hydrocarbon group, R² ishydrocarbon group which may have a substituent(s),

is β-configuration.

The C1-4 aliphatic hydrocarbon group represented by R¹ includes, forexample, C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl,butyl, sec-butyl or tert-butyl and the like; C2-4 alkenyl group such asvinyl, propenyl, butenyl or butadienyl and the like; C2-4 alkynyl groupsuch as ethynyl, propynyl or butynyl and the like.

R¹ is preferably hydrogen or C1-4 aliphatic hydrocarbon group and thelike, and is specifically, for example, hydrogen, methyl and ethyl andthe like.

The “hydrocarbon group which may have a substituent(s)” represented byR² has a same meaning as the “(1) hydrocarbon group which may have asubstituent(s)” as the substituent of the ring A described above.

R² includes preferably C1-8 aliphatic hydrocarbon group which may have asubstituent(s) (the “C1-8 aliphatic hydrocarbon group” depends in thedefinition of “C1-12 aliphatic hydrocarbon group” defined as the“hydrocarbon group” in the “(1) hydrocarbon group which may have asubstituent(s)” as the substituent of the ring A described above, andthe number of carbon can select 1 to 8 one(s)), the 3 to 8 memberedsaturated cyclic hydrocarbon group which may have a substituent(s) (the“3 to 8 membered saturated cyclic hydrocarbon group” depends in thedefinition of the “3 to 15 membered saturated cyclic hydrocarbon group”defined as the “hydrocarbon group” in the “(1) hydrocarbon group whichmay have a substituent(s)” as the substituent of the ring A describedabove, and the membered number of the ring can select 3 to 8 one(s)),phenyl which may have a substituent(s), or (C3-8 cycloalkyl)-(C1-4aliphatic hydrocarbon) group which may have a substituent(s) (here, the“C3-8 cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl, the “C1-4 aliphatic hydrocarbongroup” includes methyl, ethyl, propyl or butyl), more preferably C1-8aliphatic hydrocarbon group, or (C3-8 cycloalkyl)-(C1-4 aliphatichydrocarbon) group which may have a substituent(s). The “substituent” in“hydrocarbon group which may have a substituent(s)” as R² includespreferably, (1) the cyclic hydrocarbon group which may have asubstituent(s) (e.g., C1-4 alkyl group, amino, sulfo, halogen atom,carboxyl, cyano nitro, oxo, thioxo, hydroxyl, methoxy, trifluoromethyl,trifluoromethoxy and acetyl and the like), (2) the heterocyclic groupwhich may have a substituent(s) (e.g., C1-4 alkyl group, amino, sulfo,halogen, carboxyl, cyano, nitro, oxo, thioxo, hydroxyl, methoxy,trifluoromethyl, trifluoromethoxy and acetyl and the like), (10) halogenatom (fluorine, chlorine, bromine, iodine), (11) carboxyl, (14) oxo,(16) hydroxyl, (17) C1-8 alkoxy group such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,cyclohexylmethyloxy and benzyloxy, (here, the alkoxy group may besubstituted by such as halogen atom), (18) C3-8 cycloalkyloxy group suchas cyclohexyloxy (the cycloalkyloxy group may be substituted by such ashalogen atom), (19) the phenoxy group which may be substituted by methyland halogen atom and the like, (28) C1-6 alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl and the like,(36) C1-6 acyl group such as formyl, acetyl, propionyl and butyryl andthe like, or (37) benzoyl.

In the present description, an EP2 agonist which may have an EP3agonistic effect is a compound which may have an EP3 agonistic effectother than an EP2 agonistic effect, includes an EP2 agonist which doesnot have an EP3 agonistic effect and an EP2 agonist which has an EP3agonistic effect, and is preferably an EP2 agonist which has an EP3agonistic effect.

Moreover, the agent for regeneration and/or protection of nervescomprising an EP2 agonist which may have an EP3 agonistic effect in thepresent invention (hereinafter, abbreviated as the agent of the presentinvention) may be used by combining one or more (i) EP2 agonist(s) whichmay have an EP3 agonistic effect, with one or more agonist(s) selectedfrom (ii) EP2 agonist and (iii) EP3 agonist. The (i) EP2 agonist whichmay have an EP3 agonistic effect described above is preferably an EP2agonist which has an EP3 agonistic effect. The (ii) EP2 agonistdescribed above is preferably a compound acting on EP2 selectively,which may or may not have an EP3 agonistic effect. The (iii) EP3 agonistdescribed above is preferably a compound acting on EP3 selectively,which may or may not have an EP2 agonistic effect. For example, one ormore (i) EP2 agonist(s) which may have an EP3 agonistic effect, one ormore (ii) EP2 agonist(s) and/or one or more (iii) EP3 agonist(s) may becontained within a same pharmaceutical, one or more (i) EP2 agonist(s)which may have an EP3 agonistic effect, one or more (ii) EP2 agonist(s)and/or one or more (iii) EP3 agonist(s) are made a separatepharmaceutical and administered, and in other words may take aconfiguration of a combined medication. This combined medicationincludes simultaneous administration, and dosage by temporal difference.The dosage by temporal difference may be administered, for example, the(i) EP2 agonist which may have an EP3 agonistic effect first, and the(ii) EP2 agonist and/or the (iii) EP3 agonist later. It may beadministered, the (ii) EP2 agonist and/or the (iii) EP3 agonist first,and the (i) EP2 agonist which may have an EP3 agonistic effect later.Each administered method may be the same or different. Moreover, one ormore (i) EP2 agonist(s) which may have an EP3 agonistic effect, one ormore (ii) EP2 agonist(s) and/or one or more (iii) EP3 agonist(s) may becontained within a same pharmaceutical.

Moreover, the (i) EP2 agonist which may have an EP3 agonistic effect,the (ii) EP2 agonist and the (iii) EP3 agonist include all a compoundwhich is found newly in future as well as a known compound.

The (ii) EP2 agonist includes, for example, the compounds described inEP860430A1, WO99/33794, EP974580A1, WO95/19964, U.S. Pat. No. 5,698,598,U.S. Pat. No. 6,376,533, WO98/28264, WO99/19300, EP0911321A1,WO98/58911, WO2003/074483, WO2004/078103, WO2005/012232 and ONO-8815Ly,AH-13205, CP-533536, Butaprost, Rioprost, Misoprostol or AY23626 and thelike.

The (iii) EP3 agonist includes, for example, the compounds described inWO98/34916, JP07-233145, JP10-168056, JP11-012249, WO99/25358,JP7-215929, JP8-239356, WO97/05091, and TE¹-3356, M&B-28767, GR63799X,SC-46275, Enprostil or Sulprostone and the like.

An EP2 agonist which has an EP3 agonistic effect includes, for example,a compound represented by formula (I):

wherein all symbols have the same meanings as described above, a saltthereof, an N-oxide thereof, an S-oxide thereof, a solvate thereof or aprodrug thereof, or a cyclodextrin clathrate thereof.

The compound represented by formula (I) includes preferably the compoundrepresented by formula (I-1):

wherein the ring A¹ is 5 or 6 membered ring which may comprise 1 to 3hetero atom(s) selected from nitrogen, oxygen and sulfur in addition toX and Y, and furthermore may have a substituent(s), E¹ is oxygen oroptionally oxidized sulfur, R is C1-8 aliphatic hydrocarbon group, andthe other symbols have the same meanings as those described above, morepreferably the compound represented by formula (I-2):

wherein the ring A² is 5 or 6 membered ring which may comprise 1 to 3hetero atom(s) selected from nitrogen, oxygen and sulfur, andfurthermore may have a substituent(s), and the other symbols have thesame meanings as those described above, more preferably the compoundrepresented by formula (I-3):

wherein R¹ is hydrogen or C1-4 aliphatic hydrocarbon group, R² ishydrocarbon group which may have a substituent(s),

is α-configuration,

is β-configuration, and the other symbols have the same meanings asthose described above, and the like.

Moreover, the compound represented by formula (I-3) includes morepreferably the compound represented by formula (I-4):

wherein E² is optionally oxidized sulfur, and the other symbols have thesame meanings as those described above.

Moreover, formula (I-1) includes preferably the compound represented byformula (I-5):

wherein all symbols have the same meanings as those described above.

The compound represented by formula (I) includes preferably the compounddescribed in Examples, a salt thereof, an N-oxide thereof, an S-oxidethereof, a solvate thereof or a prodrug thereof, or a cyclodextrinclathrate thereof and the like, more preferably2-[2-{(1R,2R)-2-[(1E,4S)-5-cyclohexyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 17),2-[2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4-methyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 17-1),2-[(2-{(1R,5R)-2-oxo-5-[(1E)-8,8,8-trifluoro-4-hydroxy-4-methyl-1-octenyl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-1),2-[(2-{(1R,2R)-2-[(1E)-5-cyclopentyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-2),2-[(2-{(1R,2R)-2-[(1E)-8-fluoro-4-hydroxy-4-methyl-1-octen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-3),2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,8-dimethyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-4), 2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,8-dimethyl-1,7-nonadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-5),2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-6),2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-7-methoxy-4-methyl-1-hepten-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-10),2-[(2-{(1R,2R)-2-[(1E)-9-fluoro-4-hydroxy-4-methyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-12),2-[(2-{(2R)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 24-1),2-[(2-{(2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 24-2),2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 32),2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4,8-dimethyl-1-nonen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-2a),2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-3a),2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclobutyl-4-hydroxy-4-methyl-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-4a),2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-5a),2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-7-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 31a), or2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclobutyl-4-hydroxy-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 31-1) and the like, particularly preferably2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclohexyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 17),2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,8-dimethyl-1,7-nonadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-5),2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-6),2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4-methyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 17-1),2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 32),2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4,8-dimethyl-1-nonen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-2a), 2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-3a),2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclobutyl-4-hydroxy-4-methyl-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-4a),2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-5a),2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-7-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 31a) or2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclobutyl-4-hydroxy-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 31-1) and the like.

Moreover, the compound represented by formula (I) includes preferably2-{[2-((4S)-4-{(1E,3R)-3-[1-(4-fluorobutyl)cyclobutyl]-3-hydroxy-1-propenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylicacid (hereinafter, abbreviated as compound A),2-[(2-{(4S)-4-[(1E,3R)-8-fluoro-3-hydroxy-4,4-dimethyl-1-octenyl]-2-oxo-1,3-oxazolidin-3-yl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,(2E)-7-{(1R,2R)-2-[(1E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]-5-oxocyclopentyl}-2-heptenoicacid,2-{[2-((4S)-4-{(1E,3R)-3-hydroxy-3-[1-(3-methoxypropyl)cyclobutyl]-1-propenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylicacid,2-{[2-((4S)-4-{(1E,3R)-3-[1-(2-cyclohexylethyl)cyclobutyl]-3-hydroxy-1-propenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylicacid,2-{[2-((4S,5S)-4-{(1E)-3-hydroxy-3-[1-(3-methoxypropyl)cyclobutyl]-1-propenyl}-5-methyl-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylicacid,2-[(2-{(4S,5S)-4-[(1E)-4-hydroxy-4-methyl-1-nonenyl]-5-methyl-2-oxo-1,3-oxazolidin-3-yl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylicacid or2-[(2-{(1R,2R)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylicacid and the like.

According to the present invention, unless otherwise indicated and as isapparent for those skilled in the art, symbol

indicates that it is bound to the opposite side of the sheet (namelyα-configuration),

indicates that it is bound to the front side of the sheet (namelyβ-configuration),

indicates that it is a a-configuration, β-configuration or an optionalmixture thereof.

For example, in formula (I), a bind of X-D or a bind of Y—W may be aα-configuration, β-configuration or an optional mixture thereof.

Unless otherwise specifically mentioned, all isomers are included in thepresent invention. For example, alkyl, alkenyl, alkynyl, alkoxy,alkylthio, alkylene, alkenylene and alkynylene include straight chainand branched ones. Moreover, all of isomers due to double bond, ring andfused ring (E-, Z-, cis- and trans-forms), isomers due to presence ofasymmetric carbon(s) (R-, S-, α- and β-configuration, enantiomer anddiastereomer) and the like, optically active compounds having opticalrotation (D-, L-, d- and I-forms), polar compound by chromatographicseparation (more polar compound and less polar compound), equilibriumcompounds, rotational isomers, an optional mixture thereof and a racemicmixture are included in the present invention.

The salt is preferably a pharmacologically acceptable salt, andwater-soluble. The suitable salt includes salt with alkaline metal(e.g., potassium, sodium and the like), salt with alkaline earth metal(e.g., calcium, magnesium and the like), ammonium salt, salt withpharmaceutically acceptable organic amine (e.g., tetramethylammonium,triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine,N-methyl-D-glucamine and the like) or acid addition salt and the like.

The acid addition salt is preferably water-soluble. The suitable acidaddition salt includes, for example, inorganic acid salt such ashydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrateand the like, or organic acid salt such as acetate, lactate, tartrate,benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, isothionate, glucuronate and gluconate and the like.

The compound of the present invention and the salt thereof may beconverted to a solvate.

The solvate is preferably non-toxic and water-soluble. The suitablesolvate includes, for example, solvate of hydrate or alcoholate (e.g.,ethanolate and the like).

The compound of the present invention and the pharmaceuticallyacceptable salt thereof are all preferable. The compound described inExamples and the pharmacologically acceptable salt thereof and the like,include specifically. Moreover, the salt includes a quaternary ammoniumsalt. The quaternary ammonium salt is the compound where nitrogen of thecompound of the present invention is quarternalized by R⁰ and the like.

R⁰ is C1-8 alkyl and C1-8 alkyl substituted by phenyl.

The compound of the present invention can be converted into an N-oxideby optional methods. The N-oxide is the compound in which nitrogen ofthe compound of the present invention is oxidized and the like.

The compound of the present invention can be converted into an S-oxideby optional methods. The S-oxide is the compound in which sulfur of thecompound of the present invention is oxidized and the like.

The compound of the present invention can be converted into acyclodextrin clathrate thereof by the method described in JP50-3362,JP52-31404 or JP61-52146 using α-, β- or γ-cyclodextrin, or a mixturethereof. Converting into the corresponding cyclodextrin clathratesserves to increase the stability and solubility in water of thecompounds, and therefore it is useful in the use for pharmaceuticals.

A prodrug of the compound of the present invention includes a compoundwhich is converted to the compound of the present invention by areaction with an enzyme, gastric acid or the like in the living body.For example, with regard to a prodrug of the compound of the presentinvention, when the compound of the present invention has an aminogroup, the compounds in which the amino group was, for example,acylated, alkylated or phosphorylated (e.g., compounds in which is theamino group of the compound of the present invention was eicosanoylated,alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,acetoxymethylated, tert-butylated, and the like); when the compound ofthe present invention has a hydroxyl group, the compounds in which thehydroxyl group was, for example, acylated, alkylated, phosphorylated orborated (e.g., compounds in which the hydroxyl group of the compound ofthe present invention was acetylated, palmitoylated, propanoylated,pivaloylated, succinylated, fumarylated, alanylated ordimethylaminomethylcarbonylated); and when the compound of the presentinvention has a carboxyl group, the compounds in which the carboxylgroup was, for example, esterified or amidated (e.g., compounds in whichthe carboxyl group of the compound of the present invention was madeinto ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethylester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidylester, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester or methylamide). These compounds may beproduced by a known method per se. The prodrug of the compound of thepresent invention may be either a hydrate or a non-hydrate. The prodrugof the compound of the present invention may also be a compound which isconverted to the compound of the present invention under a physiologiccondition as described in “lyakuhin no kaihatsu, Vol. 7 (Bunshi-sekkei),pp. 163˜198 (Hirokawa-Shoten), 1990”. And the compound of the presentinvention may also be labeled by a radio isotope (such as ³H, ¹⁴C, ³⁵S,¹²⁵I, and the like).

Processes for the Preparation of the Compound of the Present Invention

The compound represented by formula (I) can be prepared by the methodswhich were properly improved and combined known methods such as a methoddescribed in JP52-27753, JP55-100360, WO03/074483, WO05/053707, Synlett2002, No. 1, 239-242 or Comprehensive Organic Transformations: A Guideto Functional Group Preparations, 2nd Edition (Richard C. Larock, JohnWiley & Sons Inc, 1999), a method described below, or a method describedin Examples.

Among the compounds represented by formula (I), a compound wherein —W is

(wherein W¹ is hydrocarbon which may have a substituent(s).), i.e., acompound represented by formula (Ia):

(wherein all symbols have the same meanings as described above.), can beprepared by the following reaction using a compound represented byformula (II):

(wherein ring A^(p), D^(p), G^(p) and J^(p) have the same meanings asring A, D, G and J respectively. With proviso that, carboxy, hydroxy,amino or thiol in ring A^(p), D^(p), G^(p) and J^(p) may be protected,if necessary. Other symbols have the same meanings as described above.),and a compound represented by formula (III):

(wherein R²⁰¹ is C1-4 alkyl, W^(1p) has the same meaning as W¹. Withproviso that, carboxy, hydroxy, amino or thiol in W^(1p) may beprotected, if necessary.), if necessary, followed by removal of theprotecting group.

This reaction is well known, and, for example, it is carried out at −15to 30° C. in the presence of sodium hydride in an organic solvent (e.g.,anhydrous tetrahydrofuran, dimethylformamide, dioxane and the like).

A deprotection reaction of the protecting group is well known, and canbe carried out by the method described below.

The protecting group of carboxy includes, for example, methyl, ethyl,allyl, tert-butyl, trichloroethyl, benzyl (Bn) and phenacyl and thelike.

The protecting group of hydroxy includes, for example, methyl, trityl,methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM),2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES),tert-butyldimethylsilyl(TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl(Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl(Alloc), or 2,2,2-trichloroethoxycarbonyl (Troc) and the like.

The protecting group of amino includes, for example, benzyloxycarbonyl,tert-butoxycarbonyl, allyloxycarbonyl (Alloc),1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl,9-fluorenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl,benzyloxymethyl (BOM) or 2-(trimethylsilyl)ethoxymethyl (SEM) and thelike.

The protective group of thiol includes, for example, benzyl,methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP),diphenylmethyl or acetyl (Ac) and the like.

With regard to the protective group for carboxyl, hydroxyl, amino orthiol, there is no particular limitation to the above ones so far as itis a group which is able to be easily and selectively detached. Forexample, a deprotection reaction may be carried out by a methodmentioned in “T. W. Greene, Protective Groups in Organic Synthesis,Wiley, New York, 1999”.

The reaction for removing the protective group for carboxyl, hydroxyl,amino or thiol is well known and its examples are as follows:

(1) a hydrolyzing reaction with an alkali,

(2) a deprotection reaction under an acidic condition,

(3) a deprotection reaction by hydrogenolysis,

(4) a deprotection reaction of silyl,

(5) a deprotection reaction using a metal, and

(6) a deprotection reaction using a metal complex.

These methods will be specifically illustrated as follows:

(1) A deprotection reaction by a hydrolyzing reaction with an alkali iscarried out, for example, about 0 to 40° C. using a hydroxide ofalkaline metal (e.g., sodium hydroxide, potassium hydroxide and lithiumhydroxide and the like), a hydroxide of alkaline earth metal (e.g.,barium hydroxide and calcium hydroxide and the like) or a carbonate(e.g., sodium carbonate and potassium carbonate and the like) or anaqueous solution thereof or a mixture thereof in an organic solvent(e.g., methanol, tetrahydrofuran and dioxane and the like);

(2) A deprotection reaction under an acidic condition is carried out,for example, about 0 to 100° C. in an organic acid (e.g., acetic acid,trifluoroacetic acid, methanesulfonic acid and p-tosylate and the like),or an inorganic acid (e.g., hydrochloric acid and sulfuric acid and thelike) or a mixture thereof (e.g., hydrogen bromide/acetic acid and thelike) in an organic solvent (e.g., dichloromethane, chloroform, dioxane,ethyl acetate and anisole and the like);

(3) A deprotection reaction by hydrogenolysis is carried out, forexample, about 0 to 200° C., under hydrogen atmosphere of ordinarypressure or high pressure, or by the using ammonium formate, in thepresence of a catalyst (e.g., palladium-carbon, palladium black,palladium hydroxide, platinum oxide and Raney nickel and the like) in asolvent (such as an ether type (e.g., tetrahydrofuran, dioxane,dimethoxyethane and diethyl ether and the like), an alcohol type (suchas methanol and ethanol and the like), a benzene type (such as benzeneand toluene and the like), a ketone type (such as acetone and methylethyl ketone and the like), a nitrile type (such as acetonitrile and thelike), an amide type (such as dimethylformamide and the like), water,ethyl acetate, acetic acid or a mixed solvent comprising two or morethereof and the like);

(4) A deprotection reaction of silyl is carried out, for example, about0 to 40° C. using tetrabutylammonium fluoride in an organic solventmiscible with water (e.g., tetrahydrofuran and acetonitrile and thelike);

(5) A deprotection reaction using metal is carried out, for example,about 0 to 40° C. with or without ultrasonic wave in the presence ofpowdery zinc in an acidic solvent (e.g., acetic acid, a buffer of pH 4.2to 7.2 or a mixed solution of the solution with an organic solvent suchas tetrahydrofuran);

(6) A deprotection reaction using a metal complex is carried out, forexample, about 0 to 40° C. using a metal complex (e.g.,tetrakistriphenylphosphine palladium (0), bis(triphenylphosphine)palladium (II) dichloride, palladium (II) acetate andtris(triphenylphosphine) rhodium (I) chloride and the like) in thepresence or absence of a phosphine agent (e.g., triphenyl phosphine andthe like) in the presence of a trap reagent (e.g., tributyltin hydride,triethylsilane, dimedone, morpholine, diethylamine and pyrrolidine andthe like), an organic acid (e.g., acetic acid, formic acid and2-ethylhexanoic acid and the like) and/or an organic acid salt (e.g.,sodium 2-ethylhexanoate and potassium 2-ethylhexanoate) in an organicsolvent (e.g., dichloromethane, dimethylformamide, tetrahydrofuran,ethyl acetate, acetonitrile, dioxane and ethanol and the like), water ora mixed solvent thereof.

Apart from the above, the deprotection reaction may also be carried out,for example, according to the methods described in T. W. Greene,Protective Groups in Organic Synthesis, Wiley, New York, 1999.

As persons skilled in the art can easily understand that the aimedcompound of the present invention is able to be easily produced by usingappropriate ones among these deprotection reactions.

Among the compounds represented by formula (I), a compound wherein —W is

(wherein all symbols have the same meanings as described above), i.e., acompound represented by formula (Ia-1):

(wherein all symbols have the same meanings as described above) can beprepared by a reduction of a compound represented by formula (IV):

(wherein all symbols have the same meanings as described above), ifnecessary, followed by removal of the protecting group.

This reaction is well known, and, for example, it is carried out about−78 to 30° C. using a reducing agent (e.g., sodium borohydride,borane-tetrahydrofuran complex and borane-dimethyl sulfide complex andthe like) in the presence or absence of (R)-2-methyl-CBS-oxazaborolidinor (S)-2-methyl-CBS-oxazaborolidin, in the presence or absence of ceriumchloride in an organic solvent (e.g., anhydrous tetrahydrofuran,methanol and dichloromethane and the like).

A deprotection reaction of the protecting group can be carried out bythe same method as described above.

Among the compounds represented by formula (I), a compound wherein —W is

(wherein all symbols have the same meanings as described above), i.e., acompound represented by formula (Ib):

(wherein all symbols have the same meanings as described above) can beprepared by the following reaction using a compound represented byformula (II) and a compound represented by formula (V):

(wherein R²⁰² is aryl (e.g., 1-phenyl-1H-tetrazolyl and phenyl and thelike), R²⁰³ is a protecting group (e.g., trimethylsilyl andtert-butyldimethylsilyl and the like), and R^(1p) and R^(2p) have thesame meanings as R¹ and R² respectively. With proviso that, carboxy,hydroxy, amino or thiol in R^(1p) and R^(2p) may be protected, ifnecessary.), if necessary, followed by removal of the protecting group.

This reaction is well known, and, for example, it is carried out about−100 to −20° C. in the presence of a base (e.g, potassium,hexamethyldisilazide, lithium diisopropylamide and butyllithium and thelike) in an organic solvent (e.g., anhydrous tetrahydrofuran,dimethoxyethane, toluene and dimethylformamide and the like).

A deprotection reaction of the protecting group can be carried out bythe same method as described above.

Moreover, the compounds represented by formula (Ib) can be prepared bythe following reaction using a compound represented by formula (II) anda compound represented by formula (VI):

(wherein R²⁰⁴, R²⁰⁵ and R²⁰⁶ are, each independently aryl (e.g., phenyland the like), Q⁻ is halogen ion and the other symbols have the samemeanings as described above), if necessary, followed by removal of theprotecting group.

This reaction is well known, and, for example, it is carried out about−100 to −20° C. in the presence of a base (e.g, lithiumdiisopropylamide, butyllithium and sodium hydride and the like) in anorganic solvent (e.g, anhydrous tetrahydrofuran, dimethoxyethane,toluene and dimethylformamide and the like).

Among the compounds represented by formula (I), a compound wherein —W is

(wherein W² is hydrocarbon group which may have a substituent(s)), i.e.,a compound represented by formula (Ic):

(wherein all symbols have the same meanings as described above.) can beprepared by a reductive amination of a compound represented by formula(II) and a compound represented by formula (VII):

(wherein W^(2p) has the same meaning as W². With proviso that, carboxy,hydroxy, amino or thiol in W^(2p) may be protected, if necessary.), ifnecessary, followed by removal of the protecting group.

This reductive amination is well known, and, for example, it is carriedout about 0 to 100° C. in the presence of a reducing agent (e.g., sodiumcyanoborohydride, sodium borohydride, sodium triacetoxyborohydride andpyridineborane and the like) in an organic solvent (e.g., methanol,ethanol, dichloromethane, tetrahydrofuran, dimethoxyethane and diethylether and the like).

A deprotection reaction of the protecting group can be carried out bythe same method as described above.

Among the compounds of the present invention, the other compounds thanthe above-described can be prepared easily by combination of the knownmethods such as the methods described in JP52-27753, JP55-100360,WO2003/74483, WO05/053707, Synlett 2002, No. 1, 239-242 or ComprehensiveOrganic Transformations: A Guide to Functional Group Preparations,2^(nd) Edition (Richard C. Larock, John Willey & Sons Inc, 1999) or themethods modified partially thereof.

The other starting compounds or the compounds used as reagent are theknown compounds, and can be prepared easily by combination of the knownmethods such as the methods described in JP52-27753, JP55-100360,WO2003/074483, WO05/053707, Synlett 2002, No. 1, 239-242 orComprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2^(nd) Edition (Richard C. Larock, John Willey & Sons Inc,1999) or Elmer J. Rauckman et. al., J. Org. Chem., vol. 41, No. 3, 1976,p 564-565 and the like. Moreover, the starting compounds may be used assalts thereof. As the salts, ones described as the salts of thecompounds of the present invention described above are used.

In each reaction of the present description, the reactions with heating,as will be apparent to those skilled in the art, it may be carried withwater bath, oil bath, sand bath and microwave and the like.

In each reaction of the present description, it may be used a solidphase reagent which was supported by polymer (e.g., polystyrene,polyacrylamide, polypropylene or polyethyleneglycol and the like).

In each reaction of the present description, the obtained products maybe purified by conventional techniques. For example, the purificationmay be carried out by distillation under atmosphere of ordinary pressureor vacuum, by high performance liquid chromatography with silica gel ormagnesium silicate, by thin layer chromatography, by ion-exchange resin,by scavenger resin, by column chromatography, by washing or byrecrystallization. The purification may be done each reaction or afterseveral reactions.

Toxicity

The toxicity of the compounds of the present invention is very low andtherefore the compounds may be considered safe for pharmaceutical use.

Application to Pharmaceuticals

An EP2 agonist which may have an EP3 agonistic effect has an effect ofregenerating and/or protecting nerves, and is therefore useful for aprevention and/or a treatment of a disease of the peripheral nervoussystem, such as lower and upper motor neuron diseases (e.g., amyotrophiclateral sclerosis, paraneoplastic syndrome, progressive bulbarparalysis, progressive muscular atrophy, primary lateral sclerosis,progressive pseudobulbar paralysis, post poliomyelitis syndrome, geneticspinal muscular atrophy (type I spinal muscular atrophy)(Werdnig-Hoffman disease), type II (intermediate) spinal muscularatrophy, type III spinal muscular atrophy (Wohlfart-Kugelberg-Welanderdisease), (type IV spinal muscular atrophy) and the like); nerve rootdiseases (e.g., hernia of intervertebral disk, spinal canal stenosis,cervical spondylosis and the like); plexus diseases (e.g., acutebrachial plexitis and the like); thoracic outlet compression syndrome;peripheral nerve disorders (e.g., mononeuropathy, multiplemononeuropathy, multiple neuropathy, Guillain-Barre syndrome, geneticneuropathy (e.g., peroneal muscular atrophy (Chalcot-Marie-Toothdisease), hypertrophic interstitial neuropathy (Dejerine-Sottasdisease), diabetic peripheral nerve disorders, neurofibromatosis (e.g.,peripheral neurofibroma (Recklinghausen disease), central nervefibromaand the like), Proteus syndrome and the like), neuromusculartransmission diseases (e.g., myasthenia gravis, amyotonia congenitasyndrome, Eaton-Lambert syndrome, botulism, systemic tetany syndrome,Isaacs syndrome and the like) and the like.

Moreover, an EP2 agonist having an EP3 agonistic effect has littleinfluence on the blood pressure and the ventricular rate, and a smallprobability of grave side effect to circulatory system.

Furthermore, the medicaments of the present invention have also aneffect of increasing cauda equina blood flow, and are useful for aprevention and/or a treatment of such as lumbago, lower limb pain, lowerlimb numbness, intermittent claudication, urocystic disorder, rectumdisorder or sexual dysfunction, and can be used an agent as a preventionand/or a therapy for such as spinal canal stenosis and/or cervicalvertebra symptom.

In the present description, the nervous protective effect includes aneffect of prevention for nervous function which deteriorates and nervousnecrosis.

The medicaments of the present invention may be administered as acombined preparation by combining with other medicaments for the purposeof 1) supplementing and/or enhancing of a prevention and/or a treatmenteffect of the compound, 2) improvement in pharmacokinetics andabsorption of the compound, and reduction of dose of the compound,and/or 3) reduction of side effect of the compound.

The combined preparation of the medicaments of the present inventionwith other medicaments may be administered in a form of a compoundedagent in which both components are compounded in a preparation or may bein a form in which they are administered by means of separatepreparations. The case of administration by means of separatepreparations includes a simultaneous administration and administrationswith time difference. In the case of administrations with timedifference, the medicament of the present invention may be firstlyadministered followed by administering the other medicament or the othermedicament may be administered firstly followed by administering themedicament of the present invention. Methods for each of theadministration are the same or different.

Diseases prevented and/or treated by the concomitant medication areespecially no limited. Any disease supplementing and/or enhancing of aprevention and/or a treatment effect of the medicaments of the presentinvention is included.

The other medicaments for the purpose of supplementing and/or enhancingof a prevention and/or a treatment effect for spinal canal stenosis ofthe medicaments of the present invention include, for example,prostaglandins, prostaglandin derivatives, nonsteroidalanti-inflammatory drugs (NSAID), vitamins, muscle relaxants,antidepressants, nitric oxide synthase inhibitors, aldose reductaseinhibitors, poly ADP-ribose polymerase (PARP) inhibitors, excitatoryamino acid receptor antagonists (e.g., NMDA receptor antagonists andAMPA receptor antagonists etc), radical scavengers, astrocytemodulators, phosphodiesterase (PDE) inhibitors and immunosuppressivedrugs (e.g., cyclosporine and FK506) and the like.

Examples of prostaglandins (hereinafter, abbreviated as PG) include PGreceptor agonists and the like. Examples of PG receptors include PGEreceptors (EP1, EP2, EP3 and EP4), PGD receptors (DP and CRTH2), PGFreceptors (FP), PGI receptors (IP), TX receptors (TP) and the like. Inaddition, examples of prostaglandin derivatives include limaprost,limaprost alfadex, beraprost and the like.

Examples of nonsteroidal anti-inflammatory drugs (NSAID) includesasapyrine, sodium salicylate, aspirin, aspirin dialuminate, diflunisal,indometacin, suprofen, ufenamate, dimethyl isopropylazulene, bufexamac,felbinac, diclofenac, tolmetin sodium, clinoril, fenbufen, nabumetone,proglumetacin, indometacin farnesil, acemetacin, proglumetacin maleate,amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol,naproxen, flurbiprofen, flurbiprofenaxetil, ketoprofen, fenoprofencalcium, tiaprofenic acid, oxaprozin, pranoprofen, loxoprofen sodium,alminoprofen, zaltoprofen, mefenamic acid, mefenamic acid aluminium,tolfenamic acid, floctafenine, ketophenylbutazone, oxyphenbutazone,piroxicam, tenoxicam, ampiroxicam, napageln ointment, epirizole,tiaramide hydrochloride, tinoridine hydrochloride, emorfazone,sulpyrine, migrenin, Saridon, Sedes G, amipylo-N, solvon, pyrinecompounding cold medicine, acetaminophen, phenacetin, dimetotiazinemesilate, cimetoride-combined drug, non-pyrine compounding cold medicineand the like.

Examples of muscle relaxants include tolperisone hydrochloride,chlorzoxazone, chlormezanone, methocarbamol, phenprobamate, pridinolmesilate, chlorphenesin carbamate, baclofen, eperisone hydrochloride,afloqualone, tizanidine hydrochloride, alcuronium chloride,suxamethonium chloride, tubocurarine chloride, dantrolene sodium,pancuronium bromide, vecuronium bromide and the like.

Antidepressants include tricyclic antidepressants or tetracyclicantidepressants. Examples of tricyclic antidepressants includeimipramine hydrochloride, desipramine hydrochloride, clomipraminehydrochloride, trimipramine maleate, amitriptyline hydrochloride,nortriptyline hydrochloride, lofepramine hydrochloride, amoxapine,dosulepin hydrochloride and the like. Examples of tetracyclicantidepressants include maprotiline, mianserin and the like.

Phosphodiesterase (PDE) inhibitors include, for example, PDE3inhibitors, PDE4 inhibitors or PDE5 inhibitors and the like. Examples ofPDE4 inhibitors include Cilomilast (brand name: Ariflo), Roflumilast(BY-217), Arofylline, OPC-6535, ONO-6126, IC-485, AWD-12-281, CC-10004,CC-1088, KW-4490, lirimilast, ZK-117137, YM-976, BY-61-9987, CC-7085,CDC-998, MEM-1414, ND-1251, Bay19-8004, D-4396, PD-168787, Atizoram(CP-80633), Cipamfylline (BRL-61063), Rolipram, NIK-616, SCH-351591 orV-11294A and the like. Examples of PDE5 inhibitors include Sildenafil,Sildenafil citrate and the like. Examples of the other PDE inhibitorsinclude NT-702 and the like.

Examples of nitric oxide synthase inhibitors includeN^(ω)-monomethyl-L-arginine (L-NMMA), N^(ω)-nitro-L-arginine (L-NNA),N^(ω)-nitro-L-arginine methylester (L-NAME), N^(ω)-amino-L-arginine(L-NAA), N^(ω)-cyclopropyl-L-arginine (L-CPA), N^(ω)-allyl-L-arginine(L-ALA), N^(ω)-nitro-L-arginine-p-nitroanilide,N^(ω),N^(ω)-dimethylarginine, 2-iminobiotin, S-methyl-L-thiocitrulline,S-ethyl-L-thiocitrulline, L-thiocitrulline, L-homothiocitrulline,2-iminopiperidine, 2-iminohomopiperidine, S-methylisothiourea,S-ethylisothiourea (EIT), S-isopropylisothiourea,S,S′-(1,3-phenylenebis(1,2-ethanediyl))bisisothiourea,2-aminothiazoline, 2-aminothiazole,N-(3-(aminomethyl)benzyl)-acetamigine,N^(δ)-(4,5-dihydrothiazol-2-yl)ornithine, N^(ω)-iminoethyl-ornithine(L-NIO), L-N⁶-(1-iminoethyl)-lysin,2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), or(+)-trans-3-imino-5-methyl-7-chloro-2-azabicyclo[4.1.0]heptane and thelike.

Examples of aldose reductase inhibitors include Tolrestat, Epalrestat,3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid,Imirestat, Zenarestat and the like.

Examples of poly ADP-ribose polymerase (PARP) inhibitors include1,5-dihydroxyisoquinoline and the like.

A weight ratio of the medicaments of the present invention and the othermedicaments is not limited in particular.

The other medicaments may be administrated with an optional combinationof two or more kinds which are same or different.

Moreover, examples of the other medicaments for supplementing and/orenhancing the preventive and/or treatment effect of the medicaments ofthe present invention include not only the known compounds but also anew compound on the basis of the mechanism described above.

In order to use the medicaments of the present invention, these arenormally administered to the entire or local part of human body orallyor parenterally.

At the same time to be different by the medicament used in the presentinvention, the doses to be administered are determined depending upon,for example, age, body weight, symptom, the desired therapeutic effect,the route of administration, and the duration of the treatment. In thehuman adult, the doses per person are generally from 1 ng to 100 mg, byoral administration, up to several times per day, and from 0.1 ng to 10mg, by parenteral administration, up to several times per day, orcontinuous administration from 1 to 24 hours per day from vein.

As mentioned above, the doses depend upon various conditions. Therefore,there are cases in which doses lower than or greater than the rangesdescribed above may be used.

The medicaments of the present invention, or the concomitant medicationscombined the medicaments of the present invention with the othermedicaments may be administered in solid preparations for internal useand liquid preparations for internal use each for oral administration,and injections, external use, suppositories, eye drops or inhalant eachfor parenteral administration and the like.

Examples of the solid preparations for internal use for oraladministration include tablets, pills, capsules, powders and granulesand the like. The capsules include hard capsules and soft capsules.

In such solid preparations for internal use, such as one or more of theactive substance(s) may be admixed with vehicles (e.g., lactose,mannitol, glucose, microcrystalline cellulose or starch and the like),binders (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone ormagnesium metasilicate aluminate and the like), disintegrants (e.g.,cellulose calcium glycolate and the like), lubricants (e.g., magnesiumstearate and the like), stabilizing agents, and solution adjuvants(e.g., glutamic acid or aspartic acid and the like) and preparedaccording to methods well known in normal pharmaceutical practice. Thesolid preparations for internal use may, if desired, be coated withcoating agents (e.g., sugar, gelatin, hydroxypropyl cellulose orhydroxypropylmethyl cellulose phthalate and the like), or be coated withtwo or more films. And further, coating may include containment withincapsules of absorbable materials such as gelatin.

Liquid preparations for internal use for oral administration includepharmaceutically acceptable solutions, suspensions and emulsions, syrupsand elixirs. In such liquid preparations, one or more of the activesubstance(s) may be dissolved, suspended or emulsified into diluent(s)commonly used in the art (e.g., purified water, ethanol or a mixturethereof and the like). Besides such liquid preparations may alsocomprise some additives, such as wetting agents, suspending agents,emulsifying agents, sweetening agents, flavor agents, aroma,preservative agents or buffering agents.

The dosage forms of the external preparation for parenteraladministration include, for example, ointment, gel, cream, poultice,patch, liniment, propellant, inhalation, spray, eye drops and nasalspray and the like. These products include one or more of the activesubstance(s) and are prepared by a known method or a usual method.

Ointments are prepared by a known method or a usual method. For example,it is prepared by triturating or dissolving one or more activesubstance(s) in a base. The substrate of ointment is selected from knownor usual one. For example, those selected from higher fatty acid orhigher fatty acid ester (e.g., adipic acid, myristic acid, palmiticacid, stearic acid, oleic acid, adipic acid ester, myristic acid ester,palmitic acid ester, stearic acid ester, oleic acid ester, and thelike), wax (e.g., beeswax, whale wax, ceresin, and the like), surfactant(e.g., polyoxyethylene alkyl ether phosphoric acid ester, and the like),higher alcohol (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, andthe like), silicon oil (e.g., dimethyl polysiloxane, and the like),hydrocarbon (e.g., hydrophilic petrolatum, white petrolatum, purifiedlanolin, liquid paraffin, and the like), glycol (e.g., ethylene glycol,diethylene glycol, propylene glycol, polyethylene glycol, macrogol, andthe like), vegetable oil (e.g., castor oil, olive oil, sesame oil,turpentine oil, and the like), animal oil (e.g., mink oil, egg yolk oil,squalane, squalene, and the like), water, absorption accelerators,agents for preventing contact dermatitis are used alone or incombination. Moreover, humectants, preservative agents, stabilizers,antioxidative agents, flavoring agents, and the like, may be contained.

A gel is prepared by a known method or a usual method. For example, itis prepared by dissolving one or more active substance(s) in a base. Thesubstrate of gel is selected from known or usual one. For example, thoseselected from lower alcohol (e.g., ethanol, isopropylalcohol, and thelike), gelling agent (e.g., carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, ethyl cellulose, and the like),neutralizing agent (e.g., triethanolamine, diisopropanolamine, and thelike), surfactant (e.g., polyethylene glycol monostearate, and thelike), gum, water, absorption accelerator, and agent for preventingcontact dermatitis are used alone or in combination. Moreover,preservative agents, antioxidative agents, flavoring agents, and thelike, may be contained.

A cream is prepared by a known method or a usual method. For example, itis prepared by dissolving or emulsifying one or more active substance(s)in a base. The substrate of cream is selected from known or usual one.For example, those selected from higher fatty acid ester, lower alcohol,hydrocarbon, polyalcohol (e.g., propylene glycol, 1,3-butylene glycol,and the like), higher alcohol (e.g., 2-hexyldecanol, cetanol, and thelike), emulsifying agent (e.g., polyoxyethylene alkyl ether, fatty acidester, and the like), water, absorption accelerator, and agent forpreventing contact dermatitis are used alone or in combination.Moreover, preservative agents, antioxidative agents, flavoring agents,and the like, may be contained.

A fomentation is prepared by a known method or a usual method. Forexample, it is prepared by dissolving one or more active substance(s) ina base to obtain a kneaded mixture and spreading the kneaded mixtureover a substrate. The substrate of fomentation is selected from known orusual one. For example, those selected from thickener (e.g., polyacrylicacid, polyvinylpyrrolidone, gum acacia, starch, gelatin, methylcellulose, and the like), humectant (e.g., urea, glycerin, propyleneglycol, and the like), filler (e.g., kaolin, zinc oxide, talc, calcium,magnesium, and the like), water, solubilizing agents, tackifiers, andagents for preventing contact dermatitis are used alone or incombination. Moreover, preservative agents, antioxidative agents,flavoring agents, and the like, may be contained.

A patch is prepared by a known method or a usual method. For example, itis prepared by dissolving one or more active substance(s) in a base, andspreading the solution over a substrate. The substrate of patch isselected from known or usual one. For example, those selected frompolymer bases, fats and oils, higher fatty acids, tackifiers, and agentsfor preventing contact dermatitis are used alone or in combination.Moreover, preservative agents, antioxidative agents, flavoring agents,and the like, may be contained.

A liniment is prepared by a known method or a usual method. For example,it is prepared by dissolving, suspending or emulsifying one or moreactive substance(s) in one or more kind(s) selected from water, alcohol(e.g., ethanol, polyethylene glycol, and the like), higher fatty acids,glycerin, soap, emulsifiers, and suspending agents. Moreover,preservative agents, antioxidative agents, flavoring agents, and thelike, may be contained.

A propellant, an inhalation and a spray may comprise in addition to adiluent used commonly, a stabilizer such as sodium bisulfite and anisotonization buffer such as sodium chloride, sodium citrate or citricacid.

Injections for parenteral administration include solutions, suspensions,emulsions and solid forms which are dissolved or suspended intosolvent(s) for injection immediately before use. The injection is usedafter dissolving, suspending, or emulsifying one or more activesubstance(s) in a solvent. As the solvent, for example, distilled waterfor injection, physiological saline, vegetable oil, and alcohols such aspropylene glycol, polyethylene glycol or ethanol are used alone or incombination. Injections may comprise stabilizing agents, solutionadjuvants (e.g., glutamic acid, aspartic acid or POLYSORBATE80(registered trade mark), and the like), suspending agents, emulsifyingagents, soothing agent, buffering agents, preservative. These injectionsmay be sterilized at a final step, or may be prepared by an asepticmanipulation. Also, these injections may also be manufactured in theform of sterile solid forms, for example, freeze-dried products, whichmay be dissolved in sterile water or some other sterile diluent(s) forinjection immediately before use.

Eye drops for parenteral administration include ophthalmic solution,ophthalmic suspension, ophthalmic emulsion, ophthalmic solution solublewhen used, and eye ointment.

These eye drops are prepared according to a known method. For example,one or more active substance(s) are dissolved, suspended or emulsifiedin a solvent before use. As the solvent for eye drops, for example,sterilized purified water, physiological saline, and other aqueoussolvent or non-aqueous agent for injection (e.g., vegetable oil, and thelike) are used alone or in combination. If necessary, the eye drops maycontain appropriately selected isotonizing agents (e.g., sodiumchloride, concentrated glycerin, and the like), buffering agents (e.g.,sodium phosphoate, sodium acetate, and the like), surfactants (e.g.,polysolvate 80 (trade name), polyoxyl 40 stearate, polyoxyethylenehardened castor oil, and the like), stabilizers (e.g., sodium citrate,sodium edetate, and the like), and antiseptics (e.g., benzalkoniumchloride, paraben, and the like). These eye drops are prepared bysterilizing in the final process, or prepared by an aseptic treatment.Also, a sterile solid, for example, a freeze-dried product can beprepared and used after dissolving in sterilized distilled water orsterilized purified water for sterile injection, or the other solventbefore use.

The dosage forms of inhalations for parenreral administration includeaerosol, powders for inhalation or liquids for inhalation. The liquidsfor inhalation may be dissolved or suspended in water or the otherappropriate solvent as needed.

These inhalations are prepared according to a known method.

For example, a liquid for inhalation is prepared by selecting properadditives from antiseptics (e.g., benzalkonium chloride or paraben, andthe like), coloring agents, buffering agents (e.g., sodium phosphate orsodium acetate, and the like), isotonizing agents (e.g., sodium chlorideor concentrated glycerin, and the like), thickening agents (e.g.,carboxyvinylpolymer, and the like), or absorption accelerators, and thelike, if necessary.

A powder for inhalation is prepared by selecting proper additives fromlubricant agents (e.g., stearin acid and the salt thereof, and thelike), binding agents, (e.g., starch, dextrin, and the like), dilutingagents (e.g., lactose, cellulose, and the like), coloring agents,antiseptics (e.g., benzalkonium chloride or p-aminobenzonic acid, andthe like), absorption accelerators, and the like, if necessary.

In case of administration of liquid for inhalation, spray (e.g.,atomizer, nebulizer, and the like) is usually used and in case ofadministration of powder for inhalation, inhalation administrationapparatus for powder agents is usually used.

The other compositions for parenteral administration includesuppositories for intrarectal administration and pessaries for vaginaladministration which comprise one or more of the active substance(s) andmay be prepared by methods known per se.

The medicaments of the present invention can apply to human andmammalian (e.g., monkey, cattle, horse, pig, sheep, dog, cat, rat,mouse, and the like) aside from human.

The Effect of the Invention

The medicaments of the present invention are useful for an origintherapy of peripheral nervous system diseases in nervous regenerativeand/or protective action being provided.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained below in detail based on Examples,but the present invention is not limited thereto.

In chromatographic separations and TLC, the solvents in parenthesis showthe eluting and developing solvents and the ratios of the solvents usedare by volume.

Unless otherwise specified, NMR data is ¹H-NMR data.

The solvents in parenthesis in NMR show the solvents used formeasurement. All the compounds described in the present description werenamed using computer program which names generally on the basis ofIUPAC, using ACD/Name Batch (registered trademark) or according to IUPACnomenclature system. For example, a compound represented by

was named2-[(2-{(1R,5R)-2-oxo-5-[(1E)-8,8,8-trifluoro-4-hydroxy-4-methyl-1-octenyl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid.

Example 1 Ethyl 4-cyclohexyl-3-hydroxy-3-methylbutanoate (compound1)

To a solution of 1-cyclohexylacetone (10 g) in 1,4-dioxane (70 mL) wereadded ethyl bromoacetate (11 mL), zinc (9.1 g) and iodine (1.7 g) atroom temperature, and the mixture was handled by ultrasonic wave for 2hours. To the reaction solution was added dropwise 1N hydrochloric acid,and the reaction solution was extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=15:1) to give thetitle compound (15.8 g) having the following physical data.

TLC: Rf 0.15 (n-hexane:ethyl acetate=10:1);

NMR (CDCl₃): δ 0.84-1.92, 2.37-2.58, 4.18.

Example 2 4-cyclohexyl-3-methyl-1,3-butanediol (compound 2)

To a suspended solution of lithium aluminium hydride (3.68 g) intetrahydrofuran (70 mL) was added dropwise the solution of compound 1(15.8 g) in tetrahydrofuran (30 mL) at 0° C., and the mixture wasstirred for 35 minutes. To the reaction solution was added ethyl acetateat 0° C. till foaming disappears, and added dropwise 5N hydrochloricacid (10 mL). The reaction solution was risen to room temperature,stirred overnight. The reaction solution was dried over anhydrousmagnesium sulfate and concentrated. The obtained residue was purified bycolumn chromatography on silica gel (n-hexane:ethyl acetate=1:1) to givethe title compound (9.0 g) having the following physical data.

TLC: Rf 0.24 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 0.84-2.13, 3.77-3.98.

Example 31-cyclohexyl-2-methyl-4-[(1-phenyl-1H-tetrazol-5-yl)thio]-2-butanol(compound 3)

To a solution of compound 2 (5.95 g) in toluene (60 mL) were addedtetrabutylammonium bromide (1.1 g) and 5N sodium hydroxide (27 mL) at 0°C., and added dropwise a suspended solution of tosyl chloride (6.7 g) intoluene (20 mL). The reaction solution was stirred for an hour at roomtemperature. To the reaction solution was added1-phenyl-1H-tetrazole-5-thiol (6.8 g), and the reaction solution wasstirred for 3.5 hours at 60° C. The reaction solution was extracted withtert-butoxymethyl. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated. The obtained residue waspurified by column chromatography on silica gel (n-hexane:ethylacetate=17:3) to give the title compound (9.56 g) having the followingphysical data.

TLC: Rf 0.45 (toluene: ethyl acetate=4:1);

NMR (CDCl₃): δ 0.84-1.87, 1.92-2.11, 3.40-3.56, 7.45-7.67.

Example 41-cyclohexyl-2-methyl-4-[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]-2-butanol(compound 4)

To a solution of compound 3 (9.56 g) in methylene chloride (138 mL) wasadded m-chloroperbenzoic acid (16.7 g) at 0° C. The reaction solutionwas stirred at room temperature overnight. To the reaction solution wasadded an aqueous saturated solution of sodium hydrogen carbonate. Thereaction solution was concentrated, and extracted with ethyl acetate.The organic layer was washed with an aqueous saturated solution ofsodium hydrogen carbonate and brine, dried over anhydrous magnesiumsulfate, and concentrated to give the title compound (10.4 g) having thefollowing physical data.

TLC: Rf 0.50 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 0.88-1.89, 1.96-2.20, 3.82-3.95, 7.55-7.74.

Example 55-({4-cyclohexyl-3-methyl-3-[(trimethylsilyl)oxy]butyl}sulfonyl)-1-phenyl-1H-tetrazole(compound 5)

To a solution of compound 4 (10.4 g) in methylene chloride (28 mL) wereadded imidazole (3.8 g) and trimethylsilyl chloride (5.3 mL) at 0° C.and the mixture was stirred for an hour. To the reaction solution wasadded water and the reaction solution was extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=9:1) to give thetitle compound (10.2 g) having the following physical data.

TLC: Rf 0.67 (n-hexane:ethyl acetate=4:1);

NMR (CDCl₃): δ 0.13, 0.84-1.81, 1.90-2.15, 3.72-3.88, 7.54-7.76.

Example 6 Ethyl2-({2-[(1R,2S,5S)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-hydroxycyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylate(compound 6)

To a solution of(3aR,4S,6aS)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)hexahydro-2H-cyclopenta[b]furan-2-one(1.00 g) in anhydrous tetrahydrofuran (9.00 mL) was added lithiumaluminium hydride (97.0 mg) at 0° C. and the mixture was stirred for 20minutes. To the reaction solution was added water at 0° C. and themixture was extracted with ethyl acetate. The reaction solution waswashed with an aqueous saturated solution of sodium tartrate and brine,dried over anhydrous sodium sulfate, and concentrated. To a solution ofmethanesulfonyl chloride (0.23 mL) in anhydrous tetrahydrofuran (5.00mL) were added the obtained residue and a solution ofdiisopropylethylamine (1.29 mL) in anhydrous tetrahydrofuran (9.00 mL)at −5° C. and the mixture was stirred for 20 minutes. To the reactionsolution was added anhydrous methanol (43.0 μL) at −5° C. and themixture was stirred for 15 minutes. To the reaction solution was addedtrimethylsilyl chloride (0.49 mL) at −5° C. and the mixture was stirredfor 10 minutes at room temperature. To the reaction solution were addedpotassium carbonate (1.10 g), potassium thioacetate (578 mg) andanhydrous dimethylformamide (20.0 mL), and the mixture was stirred for 5hours at 50° C. The reaction solution was poured into iced water,extracted with tert-butyl methyl ether, washed with water and brine,dried over anhydrous sodium sulfate and concentrated. To a solution ofthe obtained residue in ethanol (13.0 mL) were addedtri-n-butylphosphine (0.07 mL), ethyl 2-bromo-1,3-thiazole-4-carboxylate(657 mg) and potassium carbonate (770 mg) and the mixture was stirredfor an hour at room temperature. Furthermore, the reaction solution wasstirred at 50° C. overnight. The reaction solution was diluted in ethylacetate, and washed with an aqueous saturated solution of ammoniumchloride, water and brine. The reaction solution was dried overanhydrous sodium sulfate and concentrated. The obtained residue wasdissolved in tetrahydrofuran (8.60 mL). 1N hydrochloric acid (1.86 mL)was added thereto at 0° C., and the mixture was stirred for 30 minutesat room temperature. The reaction solution was diluted in ethyl acetate,washed with water and brine, dried over anhydrous sodium sulfate andconcentrated. The obtained residue was purified by column chromatographyon silica gel (n-hexane:ethyl acetate=4:1) to give the title compound(624 mg) having the following physical data.

TLC: Rf 0.36 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 1.05, 1.38, 1.77, 2.82, 3.20, 3.58, 4.41, 7.41, 7.65,7.96.

Example 7 Ethyl2-({2-[(1R,2S,5S)-2-(acetyloxy)-5-(hydroxymethyl)cyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylate(compound 7)

To a solution of compound 6 (42.2 g) in pyridine (75 mL) was addedacetic anhydride (13 mL) at 0° C., moreover added4-N,N-dimethylaminopyridine (453 mg) and the mixture was stirred for 2hours at room temperature. The reaction solution was diluted in ethylacetate, and washed with 1N hydrochloric acid and brine, dried overanhydrous sodium sulfate and concentrated. To a solution of the obtainedresidue in tetrahydrofuran (140 mL) was added a solution of 1Mtetrabutylammonium fluoride in tetrahydrofuran (110 mL) at 0° C., andthe mixture was stirred for an hour at room temperature. To the reactionsolution was added water and the mixture was extracted with ethylacetate. The organic layer was washed with water and brine, dried overanhydrous magnesium sulfate, and concentrated. The obtained residue waspurified by column chromatography on silica gel (n-hexane:ethylacetate=7:3) to give the title compound (20.2 g) having the followingphysical data.

TLC: Rf 0.48 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 1.39, 1.44-2.16, 3.16-3.37, 3.53-3.75, 4.40, 5.23-5.35,8.02.

Example 8 Ethyl2-({2-[(1R,2S,5S)-2-(acetyloxy)-5-formylcyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylate(compound 8)

To a solution of compound 7 (2.95 g) in dimethyl sulfoxide (20 mL)/ethylacetate (30 mL) were added triethylamine (7.8 mL) and sulfurtrioxide-pyridine complex (4.5 g) at 10° C., and the mixture was stirredfor an hour at room temperature. To the reaction solution was added 1Nhydrochloric acid and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and brine, dried over anhydroussodium sulfate, and concentrated to give the title compound (2.93 g)having the following physical data.

TLC: Rf 0.27 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 1.32-1.49, 1.78-2.15, 2.35-2.51, 2.69-2.84, 3.10-3.31,4.32-4.48, 5.29-5.37, 8.02, 9.67.

Example 9 Ethyl2-{[2-((1R,2S,5S)-2-(acetyloxy)-5-{(1E)-5-cyclohexyl-4-methyl-4-[(trimethylsilyl)oxy]-1-pentenyl}cyclopentyl)ethyl]thio}-1,3-thiazole-4-carboxylate(compound 9)

To a solution of compound 5 (7.20 g) in dimethoxyethane (40.0 mL) wasadded dropwise potassium bis(trimethylsilyl)amide (0.5M toluenesolution, 32.0 mL) slowly, and the mixture was stirred for 60 minutes at−78° C. To the reaction solution was added dropwise a solution ofcompound 8 (2.93 g) in dimethoxyethane (40.0 mL) slowly, and the mixturewas stirred for 25 minutes at −78° C. The reaction temperature was risento 0° C., and the reaction solution was stirred for 50 minutes. To thereaction solution was added an aqueous saturated solution of sodiumbicarbonate and the mixture was extracted with ethyl acetate. Theorganic layer was washed with an aqueous saturated solution of sodiumbicarbonate and brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was purified by column chromatographyon silica gel (n-hexane:ethyl acetate=9:1) to give the title compound(2.23 g) having the following physical data.

TLC: Rf 0.63 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 0.08-0.11, 0.79-2.24, 2.30-2.45, 3.11-3.37, 4.40,5.16-5.32, 5.35-5.53, 8.02.

Example 10 Ethyl2-[(2-{(1R,2S,5R)-2-(acetyloxy)-5-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylate(compound 10)

To a solution of compound 9 (2.23 g) in ethyl acetate (10 mL) was addeddropwise 4N hydrogen chloride/ethyl acetate solution (9.4 mL) slowly at0° C., and the mixture was stirred for 10 minutes. To the reactionsolution was added an aqueous saturated solution of sodium bicarbonateslowly and the mixture was extracted with ethyl acetate. The organiclayer was washed with an aqueous saturated solution of sodiumbicarbonate and brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was purified by column chromatographyon silica gel (n-hexane:ethyl acetate=3:1) to give the title compound(1.41 g) having the following physical data.

TLC: Rf 0.33 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 0.81-2.23, 2.31-2.50, 3.16-3.35, 4.40, 5.19-5.40,5.42-5.62, 8.02.

Example 112-[(2-{(1R,2R,5S)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-hydroxycyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 11)

To a solution of compound 10 (1.32 g) in methanol (25 mL) was addeddropwise 2N aqueous solution of sodium hydroxide (6.4 mL) at 0° C. Thereaction solution was stirred for 45 minutes at room temperature. Aftercooling to 0° C., to the reaction solution was added 2N hydrochloricacid and the mixture was extracted with ethyl acetate. The organic layerwas washed with water and brine, dried over anhydrous magnesium sulfate,and concentrated to give the title compound (1.14 g) having thefollowing physical data.

TLC: Rf 0.39 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.84-2.25, 2.33-2.53, 2.77-3.92, 4.48-4.57, 5.28-5.40,5.42-5.57, 8.08.

Example 122-[(2-{(1R,2S,5R)-2-(acetyloxy)-5-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 12)

Compound 11 (486 mg) was dissolved in pyridine (6.00 mL) and thereto wasadded acetic anhydride (0.21 mL) at 0° C. The mixture was stirred atroom temperature overnight. The reaction solution was diluted in ethylacetate, washed with 1N hydrochloric acid and brine, dried overanhydrous sodium sulfate, and concentrated to give the title compound(540 mg) having the following physical data.

TLC: Rf 0.72 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.83-2.28, 2.31-2.51, 3.06-3.53, 5.27-5.44, 5.45-5.62,8.09.

Example 13(10S,12E,13aR,16S,16aR)-10-(cyclohexylmethyl)-10-methyl-8-oxo-1,10,11,13a,14,15,16,16a-octahydro-2H,8H-7,4-(azeno)cyclopenta[j][1,5,7]oxadithiacyclopentadecin-16-ylacetate (compound 13)

To a solution of compound 12 (531 mg) in anhydrous tetrahydrofuran (11mL) were added triethylamine (0.18 mL) and 2,4,6-trichlorobenzoylchloride (0.19 mL) at 0° C., and the mixture was stirred for 30 minutesat room temperature after having stirred for an hour. To the reactionsolution was added anhydrous toluene (90 mL), and the mixture wasfiltered. The obtained filtrate was added to a solution of4-(dimethylamino)pyridine (654 mg) in anhydrous toluene (100 mL) at 100°C. and the mixture was allowed to return to room temperature. Thereaction solution was added to 1N hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over anhydrous sodium sulfate, and concentrated. Theobtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=19:1) to give the title compound (225 mg) havingthe following physical data.

TLC: Rf 0.48 (n-hexane:ethyl acetate=4:1);

NMR (CDCl₃): δ 0.84-2.30, 2.38, 2.59-2.99, 3.25-3.42, 5.24-5.37,5.37-5.53, 5.54-5.73, 7.92.

Example 142-[(2-{(1R,2R,5S)-2-[(1E,4S)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-hydroxycyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 14)

To a solution of compound 13 (225 mg) in a mixed solution of methanoland tetrahydrofuran (8.0 mL) was added 2N aqueous solution of sodiumhydroxide (0.71 mL) at 0° C., and the mixture was stirred for an hour atroom temperature. To the reaction solution was added 2N hydrochloricacid (2.0 mL). The mixture was extracted with ethyl acetate, and washedwith water and brine. The reaction solution was dried over anhydroussodium sulfate and concentrated to give the title compound (214 mg)having the following physical data.

TLC: Rf 0.39 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.85-2.26, 2.34-2.56, 2.83-3.01, 3.18-3.69, 4.49-4.56,5.34, 5.40-5.56, 8.07.

Example 15 Ethyl2-[(2-{(1R,2R,5S)-2-[(1E,4S)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-hydroxycyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylate(compound 15)

To a solution of compound 14 (214 mg) in N,N-dimethylformamide (3.0 mL)were added potassium carbonate (261 mg) and iodoethane (0.08 mL) at 0°C., and the mixture was stirred for 3 hours at room temperature. To thereaction solution was added an aqueous saturated solution of sodiumchloride, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over anhydrous sodiumsulfate, and concentrated. The obtained residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=3:2) to give thetitle compound (225 mg) having the following physical data.

TLC: Rf 0.18 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 0.83-2.12, 2.16, 2.30-2.46, 2.82-2.95, 3.52-3.67, 4.39,4.44-4.51, 5.24-5.52, 7.97.

Example 16 Ethyl2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylate(compound 16)

To a solution of compound 15 (225 mg) in dimethyl sulfoxide (2.0mL)/ethyl acetate (4.0 mL) solution was added diisopropylethylamine(0.65 mL) and sulfur trioxide-pyridine complex (298 mg) at 10° C., andthe mixture was stirred for 30 minutes. To the reaction solution wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with 1N hydrochloric acid, water and brine,dried over anhydrous sodium sulfate, and concentrated. The obtainedresidue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=7:3) to give the title compound (188 mg) havingthe following physical data.

TLC: Rf 0.26 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 0.81-2.28, 2.31-2.61, 3.37-3.47, 4.41, 5.47, 5.60-5.76,8.01.

Example 172-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclohexyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 17): hereinafter, abbreviated as compound 17

To a solution of compound 16 (188 mg) in dimethyl sulfoxide (20mL)/phosphate-buffered solution (20 mL) was added porcine liver esterase(1.1 mL), and the mixture was stirred at room temperature overnight. Thereaction solution was diluted in ethyl acetate, and washed with anaqueous saturated solution of ammonium sulfate, 1N hydrochloric acid,water and brine. The reaction solution was dried over anhydrous sodiumsulfate, and concentrated. The obtained residue was purified by columnchromatography on silica gel (ethyl acetate) to give the title compound(156 mg) having the following physical data.

TLC: Rf 0.61 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.85-1.87, 1.90-2.30, 2.32-2.58, 3.36, 5.52, 5.62-5.77,8.11.

Example 17 (1)2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4-methyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 17)

By the same procedure as described in Example 9→Example 10→Example11→Example 12→Example 13→Example 14→Example 15→Example 16→Example 17using5-({3-methyl-3-[(trimethylsilyl)oxy]octyl}sulfonyl)-1-phenyl-1H-tetrazoleinstead of compound 5, the title compound having the following physicaldata was obtained.

TLC: Rf 0.60 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.84-0.95, 1.09-1.79, 1.86-2.62, 3.36, 5.52, 5.62-5.77,8.11.

Example 18 (1)˜(19)

By the same procedure as described in Example 9→Example 10→Example11→Example 15→Example 16→Example 17 using the corresponding compoundinstead of compound 5, the following compounds were obtained.

Example 18 (1)2-[(2-{(1R,5R)-2-oxo-5-[(1E)-8,8,8-trifluoro-4-hydroxy-4-methyl-1-octenyl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-1)

TLC: Rf 0.66 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.19, 1.43-1.76, 1.85-2.61, 3.10, 3.30-3.45, 5.53,5.61-5.79, 8.11.

Example 18 (2)2-[(2-{(1R,2R)-2-[(1E)-5-cyclopentyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-2)

TLC: Rf 0.55 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.99-2.62, 3.36, 5.51, 5.60-5.78, 8.10.

Example 18 (3)2-[(2-{(1R,2R)-2-[(1E)-8-fluoro-4-hydroxy-4-methyl-1-octen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-3)

TLC: Rf 0.42 (ethyl acetate:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.18, 1.39-2.33, 2.33-2.58, 3.36, 4.34-4.40, 4.47-4.60,5.46-5.60, 5.60-5.76, 8.10.

Example 18 (4)2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,8-dimethyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-4)

TLC: Rf 0.63 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.73-0.96, 0.99-1.77, 1.83-2.62, 2.62-3.62, 3.19-3.48,5.45-5.60, 5.61-5.78, 8.11.

Example 18 (5)2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,8-dimethyl-1,7-nonadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-5)

TLC: Rf 0.50 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.17-1.21, 1.44-1.56, 1.62, 1.68, 1.91-2.32, 2.36-2.53,3.36, 5.03-5.15, 5.53, 5.62-5.77, 8.11.

Example 18 (6)2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-6)

TLC: Rf 0.53 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.18-1.22, 1.54-1.70, 1.73-1.75, 1.92-2.31, 2.35-2.58,3.36, 4.66-4.75, 5.53, 5.63-5.78, 8.11.

Example 18 (7)2-[(2-{(1R,2R)-2-[(1E)-6-cyclobutyl-4-hydroxy-4-methyl-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid (compound 18-7)

TLC: Rf 0.49 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.12-1.21, 1.22-2.83, 3.26-3.45, 5.44-5.60, 5.60-5.77,8.11.

Example 18 (8)2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-8)

TLC: Rf 0.47 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.83-0.93, 1.11-1.31, 1.39-1.57, 1.57-1.78, 1.90-2.30,2.34-2.59, 3.36, 5.52, 5.59-5.78, 8.10.

Example 18 (9)2-[(2-{(1R,2R)-2-[(1E)-6-cyclopropyl-4-hydroxy-4-methyl-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid (compound 18-9)

TLC: Rf 0.30 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ −0.21-0.15, 0.30-0.54, 0.52-0.73, 0.80-4.57, 1.02-1.39,1.46-1.77, 1.85-2.34, 2.33-2.59, 3.21-3.47, 5.43-5.58, 5.59-5.79, 8.10.

Example 18 (10)2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-7-methoxy-4-methyl-1-hepten-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid (compound 18-10)

TLC: Rf 0.33 (methylene chloride:methanol=4:1);

NMR (CDCl₃): δ 1.16, 1.46-2.61, 3.26-3.56, 5.43-5.57, 5.60-5.80, 8.07.

Example 18 (11)2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1-octen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-11)

TLC: Rf 0.40 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.02-1.18, 1.40-1.53, 1.58-1.79, 1.89-2.61, 3.28-3.45,5.57, 5.68-5.85, 8.11.

Example 18 (12)2-[(2-{(1R,2R)-2-[(1E)-9-fluoro-4-hydroxy-4-methyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-12)

TLC: Rf 0.59 (ethyl acetate:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.17, 1.32-2.63, 3.37, 4.36, 4.52, 5.46-5.59, 5.61-5.80,8.11.

Example 18 (13)2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1-nonen-7-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-13)

TLC: Rf 0.35 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.18, 1.56-1.74, 1.77, 1.88-2.60, 3.36, 3.70-4.00, 5.51,5.68, 8.10.

Example 18 (14)2-[(2-{(1R,2R)-2-[(1E)-10-fluoro-4-hydroxy-4-methyl-1-decen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid (compound 18-14)

TLC: Rf 0.50 (ethyl acetate:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.18, 1.22-2.61, 3.26-3.46, 4.35, 4.51, 5.43-5.60,5.59-5.78, 8.10.

Example 18 (15)2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1-octen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-15)

TLC: Rf 0.38 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.78-1.00, 1.15-1.20, 1.22-1.54, 1.57-1.80, 1.84-2.35,2.34-2.61, 2.68-4.99, 3.17-3.52, 5.44-5.60, 5.61-5.79, 8.11.

Example 18 (16)2-[(2-{(1R,2R)-2-[(1E)-5-cyclobutyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-16)

TLC: Rf 0.55 (methylene chloride:methanol=4:1);

NMR (CDCl₃): δ 1.09, 1.49-2.60, 3.22-3.48, 5.50, 5.59-5.79, 8.10.

Example 18 (17)2-[(2-{(1R,2R)-2-[(1E,5E)-4-hydroxy-4-methyl-1,5-nonadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-17)

TLC: Rf 0.62 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.81-0.96, 1.19-1.45, 1.57-1.75, 1.86-2.59, 3.28-3.45,5.42-5.68, 8.08-8.14.

Example 18 (18)2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1-decen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-18)

TLC: Rf 0.53 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.23-4.53, 0.74-1.00, 1.03-1.55, 1.55-1.78, 1.84-2.64,3.15-3.54, 5.43-5.59, 5.60-5.77, 8.09.

Example 18 (19)2-[(2-{(1R,2R)-2-[(1E,6E)-4-hydroxy-4-methyl-1,6-nonadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 18-19)

TLC: Rf 0.48 (ethyl acetate:methanol:water=40:10:1);

NMR (CDCl₃): δ 0.99, 1.12-1.19, 1.56-1.77, 1.89-2.61, 3.36, 5.23-5.90,8.09.

Example 19 Ethyl2-({2-[(1R,2R)-2-((1E,5E)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-nonadiene-1-yl)-5-oxocyclopenty}ethyl]thio)-1,3-thiazole-4-carboxylate(compound 19)

By the same procedure as described in Example 9→Example 11→Example15→Example 16 using1-phenyl-5-({(4E)-3-[(trimethylsilyl)oxy]-4-octen-1-yl}sulfonyl)-1H-tetrazoleinstead of compound 5, the title compound (210 mg) having the followingphysical data was obtained.

TLC: Rf 0.50 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ −0.03-0.08, 0.83-0.96, 1.33-1.46, 1.56-1.70, 1.82-2.54,3.21-3.54, 3.96-4.41, 4.40, 5.23-5.69, 8.02.

Example 202-[(2-{(1R,2R)-2-[(1E,5E)-4-hydroxy-1,5-nonadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 20)

A solution of compound 19 (119 mg) and p-toluenesulfonic acidmonohydrate (97 mg) in methanol (4.0 mL) was stirred for 30 minutes atroom temperature. After the reaction solution was diluted in ethylacetate, it was washed with water and brine, dried over anhydrous sodiumsulfate, and concentrated. The obtained residue was purified by columnchromatography on silica gel (ethyl acetate:n-hexane=1:2→1:1). By thesame procedure as described in Example 17 using the obtained compoundinstead of compound 16, the title compound having the following physicaldata was obtained.

TLC: Rf 0.58 (methylene chloride:methanol=4:1);

NMR (CDCl₃): δ 0.89, 1.30-1.48, 1.54-1.77, 1.88-2.58, 3.21-3.55,3.98-4.29, 5.26-5.86, 8.10.

Example 20 (1)˜Example 20 (3)

By the same procedure as described in Example 9→Example 11→Example15→Example 16→Example 20 using the corresponding compound instead ofcompound 5, the following compounds were obtained.

Example 20 (1)2-[(2-{(1R,2R)-2-[(1E)-6-cyclobutyl-4-hydroxy-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 20-1)

TLC: Rf 0.51 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.30-2.34, 2.36-2.55, 3.27-3.42, 3.59-3.71, 5.54,5.59-5.71, 8.08-8.14.

Example 20 (2)2-[(2-{(1R,2R)-2-[(1E,5E)-4-hydroxy-5-methyl-1,5-nonadien-1-yl]-5-oxocyclopentyl}ethypthio]-1,3-thiazole-4-carboxylicacid (compound 20-2)

TLC: Rf 0.55 (methylene chloride:methanol=4:1);

NMR (CDCl₃): δ 0.89, 1.30-1.43, 1.53-1.74, 1.86-2.60, 3.22-3.49,3.99-4.09, 5.37, 5.43-5.64, 8.09.

Example 20 (3)2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-1-nonen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 20-3)

TLC: Rf 0.26 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.90-1.06, 1.41-1.59, 1.60-2.27, 2.34-2.60, 3.14-3.51,4.28-4.55, 5.57, 5.63-5.80, 8.09-8.12.

Example 21(5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(2-hydroxyethyl)-2-pyrrolidinone(compound 21)

To a solution of (5R)-5-(hydroxymethyl)-2-pyrrolidinone (50 g) indimethylformamide (434 mL) were added imidazole (35 g) andtert-butyldimethylsilyl chloride (68.7 g) on ice bath, and the mixturewas stirred for 1.5 hours at room temperature. The reaction solution waspoured into cold water, and extracted with ethyl acetate. The obtainedorganic layer was washed with water and brine, dried over anhydrousmagnesium sulfate, and concentrated. To a solution of the obtainedresidue in anhydrous tetrahydrofuran (869 mL) was added potassiumtert-butoxide (53.6 g) on ice bath, and the mixture was stirred for 10minutes. To the reaction solution was added dropwise ethyl bromoacetate(53 mL), and the mixture was stirred for an hour at room temperature.The reaction solution was poured into an aqueous saturated solution ofammonium chloride which was cooled to 0° C., and extracted with ethylacetate. The obtained organic layer was washed with brine, dried overanhydrous magnesium sulfate, and concentrated. To a solution of theobtained residue in a solution (869 mL) of tetrahydrofuran/ethanol (7:1)was added sodium borohydride (49 g) and methanol (30 mL) on ice bath,and stirred for 2 hours. The reaction solution was poured into anaqueous saturated solution of ammonium chloride which was cooled to 0°C., and extracted with ethyl acetate. The obtained organic layer waswashed with water and brine, dried over anhydrous sodium sulfate, andconcentrated to give the title compound (118.8 g) having the followingphysical data. This compound was used for the next reaction withoutbeing purified.

TLC: Rf 0.15 (ethyl acetate);

NMR (CDCl₃): δ 0.07, 0.89, 1.60, 1.75-1.94, 2.06-2.24, 2.24-2.58,3.21-4.07.

Example 22S-{2-[(2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-oxo-1-pyrrolidinyl]ethyl}ethanethioate(compound 22)

To a solution of compound 21 (118.8 g) and triethylamine (72.6 mL) intetrahydrofuran (869 mL) was added dropwise methanesulfonyl chloride (37mL) on ice bath, and the mixture was stirred for 5 minutes at 0° C. Tothe reaction solution were added dimethylformamide (1.2 L), potassiumcarbonate (90 g) and thioacetic acid potassium (99 g), and the mixturewas stirred for 50 minutes at 50° C. The reaction solution was pouredinto cold water, and extracted with ethyl acetate. The obtained organiclayer was washed with brine, dried over anhydrous magnesium sulfate, andconcentrated to give the title compound (143.99 g) having the followingphysical data. This compound was used for the next reaction withoutbeing purified.

TLC: Rf 0.66 (ethyl acetate);

NMR (CDCl₃): δ 0.05, 0.06, 0.88, 1.77-1.94, 1.99-2.19, 2.19-2.57,2.93-3.14, 3.14-3.32, 3.40-3.96.

Example 23 Butyl2-({2-[(2R)-2-(hydroxymethyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylate(compound 23)

To a solution of compound 22 (143.99 g) in n-butanol (869 mL) were addedethyl-2-bromo-1,3-thiazole-4-carboxylate (102.53 g), tributylphosphine(10.7 mL) and potassium carbonate (96 g) on ice bath, and the mixturewas stirred at 80° C. overnight. The reaction solution was poured intocold water, and extracted with ethyl acetate. The obtained organic layerwas washed with brine, dried over anhydrous magnesium sulfate, andconcentrated. To a solution of the obtained residue (205.75 g) in ethylacetate (489 mL) were added a solution (244 mL) of 4N hydrochloricacid/ethyl acetate and n-butanol (400 mL), and the mixture was stirredfor an hour at 45° C. To the reaction solution was added toluene, andthe mixture was concentrated. The obtained residue which was divided byhalf into twice was purified by column chromatography on silica gel(ethyl acetate:methanol=9:1) to give the title compound (143 g) havingthe following physical data.

TLC: Rf 0.58 (ethyl acetate:methanol=9:1);

NMR (CDCl₃): δ 0.35-4.75, 0.97, 1.35-1.54, 1.65-1.81, 1.82-1.98,2.06-2.23, 2.23-2.57, 3.30-3.96, 4.33, 7.99.

Example 24 (1)˜Example 24 (3)

By the same procedure as described in Example 8→Example 9→Example10→Example 11 using compound 5, or5-({3,6-dimethyl-3-[(trimethylsilyl)oxy]heptyl}sulfonyl)-1-phenyl-1H-tetrazoleor5-({3-methyl-3-[(trimethylsilyl)oxy]-4-nonyn-1-yl}sulfonyl)-1-phenyl-1H-tetrazoleinstead of compound 5, and compound 23 instead of compound 7, thefollowing compounds were obtained.

Example 24 (1)2-[(2-{(2R)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 24-1)

TLC: Rf 0.30 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.81-1.89, 2.11-2.60, 3.23-3.44, 3.44-3.62, 3.72-3.90,4.04-4.22, 5.36, 5.71-5.97, 8.09.

Example 24 (2)2-[(2-{(2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 24-2)

TLC: Rf 0.28 (ethyl acetate:methanol:acetic acid=8:1:1);

NMR (CDCl₃): δ 0.67-1.01, 1.03-1.32, 1.34-1.58, 1.62-1.88, 2.10-2.59,3.00-4.95, 3.18-3.43, 3.43-3.59, 3.71-3.90, 4.05-4.22, 5.19-5.48,5.70-5.97, 8.09.

Example 24 (3)2-[(2-{(2R)-2-[(1E)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 24-3)

TLC: Rf 0.50 (ethyl acetate:methanol:acetic acid=8:1:1);

NMR (CDCl₃): δ 0.78-0.99, 1.28-1.57, 1.65-1.89, 2.08-2.61, 2.75-4.84,3.19-3.46, 3.44-3.67, 3.68-3.94, 4.01-4.25, 5.20-5.58, 5.71-6.06, 8.08.

Example 252-[(2-{(1R,2R)-2-[(1E,4R)-5-cyclohexyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25)

By the same procedure as described in Example 14→Example 15→Example16→Example 17 using(10R,12E,13aR,16S,16aR)-10-(cyclohexylmethyl)-10-methyl-8-oxo-1,10,11,13a,14,15,16,16a-octahydro-2H,8H-7,4-(azeno)cyclopenta[j][1,5,7]oxadithiacyclopentadecin-16-ylacetate (more polar) which was obtained by the same procedure asdescribed in Example 13 instead of compound 13, the title compoundhaving the following physical data was obtained.

TLC: Rf 0.61 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.77-1.87 (m, 18H), 1.86-2.59 (m, 8H), 3.24-3.47 (m, 4H),5.52 (dd, J=15.40, 7.70 Hz, 1H), 5.61-5.76 (m, 1H), 8.11 (s, 1H).

Example 25 (1)˜Example 25 (9)

By the same procedure as described in Example 9→Example 10→Example11→Example 12→Example 13→Example 14→Example 15→Example 16→Example 17using the corresponding compounds instead of compound 5, the followingcompounds were obtained.

Example 25 (1)2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4-methyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-1)

TLC: Rf 0.60 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.89 (t, J=6.68 Hz, 3H), 1.11-1.78 (m, 12H), 1.86-2.61(m, 9H), 3.24-3.47 (m, 4H), 5.53 (dd, J=15.00, 8.25 Hz, 1H), 5.62-5.77(m, 1H), 8.11 (s, 1H).

Example 25 (2)

Less polar:2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4,8-dimethyl-1-nonen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-2a)

TLC: Rf 0.64 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.95 (d, J=6.60 Hz, 6H), 1.46 (s, 3H), 1.58-1.88 (m, 2H),1.91-2.26 (m, 7H), 2.27-2.57 (m, 4H), 3.20-3.53 (m, 2H), 4.49-6.26 (m,2H), 5.56 (dd, J=15.21, 7.88 Hz, 1H), 5.65-5.83 (m, 1H), 8.10 (s, 1H).

More polar:2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4,8-dimethyl-1-nonen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-2b)

TLC: Rf 0.61 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.93 (d, J=6.97 Hz, 6H), 1.48 (s, 3H), 1.57-1.84 (m, 2H),1.87-2.26 (m, 7H), 2.26-2.62 (m, 4H), 3.23-3.54 (m, 2H), 3.63-5.17 (m,2H), 5.56 (dd, J=15.21, 8.25 Hz, 1H), 5.67-5.88 (m, 1H), 8.09 (s, 1H).

Example 25 (3)

Less polar:2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-3a)

TLC: Rf 0.53 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.89 (d, J=6.59 Hz, 6H), 1.11-1.32 (m, 5H), 1.39-1.56 (m,3H), 1.56-1.76 (m, 1H), 1.88-2.28 (m, 7H), 2.35-2.57 (m, 2H), 3.36 (t,J=7.32 Hz, 2H), 5.52 (dd, J=15.57, 7.68 Hz, 1H), 5.61-5.78 (m, 1H), 8.10(s, 1H).

More polar:2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-3b)

TLC: Rf 0.53 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.88 (d, J=6.59 Hz, 6H), 1.09-1.33 (m, 5H), 1.36-1.56 (m,3H), 1.56-1.75 (m, 1H), 1.90-2.32 (m, 7H), 2.32-2.56 (m, 2H), 3.35 (t,J=7.68 Hz, 2H), 5.51 (dd, J=15.21, 7.89 Hz, 1H), 5.62-5.75 (m, 1H), 8.09(s, 1H).

Example 25 (4)

Less polar:2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclobutyl-4-hydroxy-4-methyl-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-4a)

TLC: Rf 0.64 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.16 (s, 3H), 1.29-2.30 (m, 19H), 2.33-2.58 (m, 2H), 3.36(t, J=7.50 Hz, 2H), 5.52 (dd, J=16.08, 8.04 Hz, 1H), 5.61-5.80 (m, 1H),8.11 (s, 1H).

More polar:2-[(2-{(1R,2R)-2-[(1E,4R)-6-cyclobutyl-4-hydroxy-4-methyl-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-4b)

TLC: Rf 0.64 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.17 (s, 3H), 1.25-2.32 (m, 19H), 2.34-2.60 (m, 2H), 3.36(t, J=7.14 Hz, 2H), 5.53 (dd, J=15.36, 7.86 Hz, 1H), 5.60-5.77 (m, 1H),8.11 (s, 1H).

Example 25 (5)

Less polar:2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-5a)

TLC: Rf 0.63 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.38-3.85 (m, 2H), 0.90 (t, J=7.14 Hz, 3H), 1.27-1.54 (m,7H), 1.55-1.78 (m, 1H), 1.93-2.62 (m, 11H), 3.10-3.60 (m, 2H), 5.47-5.65(m, 1H), 5.66-5.86 (m, 1H), 8.11 (s, 1H).

More polar:2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-5b)

TLC: Rf 0.63 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.35-3.01 (m, 2H), 0.89 (t, J=7.14 Hz, 3H), 1.17-1.54 (m,7H), 1.54-1.76 (m, 1H), 1.89-2.65 (m, 11H), 3.20-3.53 (m, 2H), 5.50-5.64(m, 1H), 5.68-5.88 (m, 1H), 8.11 (s, 1H).

Example 25 (6)2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclopentyl-4-hydroxy-4-methyl-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-6)

TLC: Rf 0.47 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.95-1.73 (m, 17H), 1.76-2.34 (m, 8H), 2.37-2.63 (m, 2H),3.35 (t, J=7.68 Hz, 1H), 3.52-3.66 (m, 2H), 5.53 (dd, J=15.18, 7.86 Hz,1H), 5.63-5.80 (m, 1H), 8.11 (s, 1H).

Example 25 (7)2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-9,9,9-trifluoro-4-hydroxy-4-methyl-1-nonen-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-7)

TLC: Rf 0.43 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.17 (s, 3H), 1.32-1.79 (m, 7H), 1.87-2.26 (m, 9H),2.34-2.58 (m, 2H), 3.28-3.45 (m, 2H), 5.51 (dd, J=15.00, 8.04 Hz, 1H),5.60-5.77 (m, 1H), 8.09 (s, 1H).

Example 25 (8)2-[(2-{(1R,2R)-2-[(1E,4S,7S)-4-hydroxy-4,7-dimethyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-8)

TLC: Rf 0.61 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.76-0.96 (m, 6H), 1.04-1.80 (m, 11H), 1.91-2.31 (m, 7H),2.33-2.58 (m, 2H), 3.36 (t, J=7.32 Hz, 2H), 5.52 (dd, J=15.36, 8.04 Hz,1H), 5.62-5.76 (m, 1H), 8.11 (s, 1H).

Example 25 (9)2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,7,7-trifluoro-4-hydroxy-4-methyl-1-hepten-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 25-9)

TLC: Rf 0.55 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.19 (s, 3H), 1.55-1.81 (m, 3H), 1.88-2.31 (m, 9H),2.35-2.57 (m, 2H), 3.37 (t, J=6.77 Hz, 2H), 5.53 (dd, J=15.18, 7.68 Hz,1H), 5.60-5.75 (m, 1H), 8.10 (s, 1H).

Example 26 Ethyl2-({2-[(1R,2S,5R)-2-(acetoxy)-5-((1E)-4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-methyl-1,7-octadien-1-yl)cyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylate(compound 26)

By the same procedure as described in Example 9 using5-[(3-{(1,1-dimethylethyl)(dimethyl)silyl]oxy}-6-methyl-6-heptan-1-yl)sulfonyl]-1-phenyl-1H-tetrazoleinstead of compound 5, the title compound (389 mg) having the followingphysical data was obtained.

TLC: Rf 0.51 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 0.01-0.12 (m, 6H), 0.80-0.97 (m, 9H), 1.30-2.23 (m, 22H),2.24-2.48 (m, 1H), 3.07-3.37 (m, 2H), 3.57-3.73 (m, 1H), 4.39 (q, J=7.14Hz, 2H), 4.57-4.74 (m, 2H), 5.13-5.34 (m, 2H), 5.36-5.55 (m, 1H), 8.00(s, 1H).

Example 272-({2-[(1R,2R,5S)-2-((1E)-4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-methyl-1,7-octadien-1-yl)-5-hydroxycyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylicacid (compound 27)

To a solution of compound 26 (389 mg) in ethanol (3 mL) was added 2Naqueous solution of sodium hydroxide, and the mixture was stirred for 90minutes at room temperature. The reaction solution was cooled on icebath, adjusted with pH 5 by the addition of 5% aqueous solution ofcitric acid, and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over anhydrous magnesium sulfate, andconcentrated to give the title compound (314 mg) having the followingphysical data.

TLC: Rf 0.38 (methylene chloride:methanol=4:1);

NMR (CDCl₃): δ 0.04 (s, 6H), 0.88 (s, 9H), 1.30-2.24 (m, 15H), 2.27-2.50(m, 1H), 2.74-2.97 (m, 1H), 3.47-3.78 (m, 3H), 4.47-4.59 (m, 1H),4.60-4.75 (m, 2H), 5.14-5.32 (m, 1H), 5.32-5.54 (m, 1H), 8.06 (s, 1H).

Example 28 Ethyl2-({2-[(1R,2R,5S)-2-((1E)-4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-methyl-1,7-octadien-1-yl)-5-hydroxycyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylate(compound 28)

To a solution of compound 27 (314 mg) in N,N-dimethylformamide (3 mL)were added potassium carbonate (334 mg) and iodoethane (964), and themixture was stirred for 5 hours at room temperature. The reactionsolution was diluted in ethyl acetate, washed with water and brine,dried over anhydrous magnesium sulfate, and concentrated to give thetitle compound (315 mg) having the following physical data.

TLC: Rf 0.39 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 0.04 (s, 6H), 0.88 (s, 9H), 1.26-2.10 (m, 16H), 2.16 (t,J=6.50 Hz, 2H), 2.23-2.45 (m, 1H), 2.76-2.98 (m, 1H), 3.48-3.74 (m, 3H),4.38 (q, J=7.14 Hz, 2H), 4.42-4.51 (m, 1H), 4.58-4.73 (m, 2H), 5.15-5.30(m, 1H), 5.30-5.50 (m, 1H), 7.95 (s, 1H).

Example 29 Ethyl2-({2-[(1R,2R)-2-((1E)-4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-methyl-1,7-octadien-1-yl)-5-oxocyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylate(compound 29)

To a solution of compound 28 (315 mg) in ethyl acetate (1.5 mL) wereadded dimethyl sulfoxide (1.5 mL), diisopropylethylamine (0.84 mL) andsulfur trioxide-pyridine complex (387 mg) under a water bath, and themixture was stirred for an hour. To the reaction solution was added 5%aqueous solution of citric acid, and the mixture was stirred intensely.The reaction solution was extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate, and concentrated. The obtained residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=90:10→67:33) togive the title compound (279 mg) having the following physical data.

TLC: Rf 0.51 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 0.01-0.12 (m, 6H), 0.88 (s, 9H), 1.39 (t, J=7.14 Hz, 3H),1.46-1.68 (m, 3H), 1.70 (s, 3H), 1.81-2.53 (m, 11H), 3.24-3.55 (m, 2H),3.59-3.76 (m, 1H), 4.39 (q, J=7.14 Hz, 2H), 4.58-4.74 (m, 2H), 5.32-5.50(m, 1H), 5.50-5.71 (m, 1H), 8.02 (s, 1H).

Example 30

Less polar: Ethyl2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-7-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethypthio]-1,3-thiazole-4-carboxylate(compound 30a)

More polar: Ethyl2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-7-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylate(compound 30b)

A solution of compound 29 (279 mg) in methanol (5 mL) was cooled on icebath and thereto was added p-toluenesulfonic acid (17.6 mg). The mixturewas stirred for 6 hours at room temperature. To the reaction solutionwas added ice water. The mixture was stirred intensely, and extractedwith ethyl acetate. The obtained organic layer was washed with water andbrine, dried over anhydrous magnesium sulfate, and concentrated. Theobtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=75:25→55:45) to give the title compounds(compound 30a: 57 mg, compound 30b: 66 mg) having the following physicaldata.

Compound 30a:

TLC: Rf 0.50 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 1.39 (t, J=7.14 Hz, 3H), 1.48-1.69 (m, 3H), 1.72 (s, 3H),1.79-1.96 (m, 1H), 1.96-2.58 (m, 10H), 3.25-3.43 (m, 1H), 3.43-3.58 (m,1H), 3.58-3.75 (m, 1H), 4.38 (q, J=7.14 Hz, 2H), 4.60-4.76 (m, 2H), 5.51(dd, J=15.20, 8.00 Hz, 1H), 5.68 (ddd, J=15.20, 7.50, 6.40 Hz, 1H), 7.99(s, 1H).

Compound 30b:

TLC: Rf 0.46 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 1.39 (t, J=7.14 Hz, 3H), 1.48-1.70 (m, 3H), 1.72 (s, 3H),1.79-2.60 (m, 11H), 3.42 (t, J=7.32 Hz, 2H), 3.52-3.71 (m, 1H), 4.38 (q,J=7.14 Hz, 2H), 4.62-4.76 (m, 2H), 5.51 (dd, J=15.30, 8.00 Hz, 1H), 5.68(dt, J=15.30, 6.80 Hz, 1H), 8.00 (s, 1H).

Example 31

Less polar origin:2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-7-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 31a)

More polar origin:2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-7-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 31b)

To a solution of compound 30a (57 mg) in ethanol (2 mL) were addedphosphate-buffered solution (10 mL) and porcine liver esterase (0.70mL), and the mixture was stirred for 2 days at room temperature. To thereaction solution was added an aqueous solution of ammonium sulfate, andthe mixture was stirred intensely. To the reaction solution was added anaqueous solution of citric acid, and the mixture was extracted withethyl acetate. The organic layer was washed with water and brine, driedover anhydrous magnesium sulfate, and concentrated. The obtained residuewas purified by column chromatography on silica gel (methylenechloride:methanol=9:1) to give compound 31a (52 mg).

By the same procedure as described above using compound 30b (66 mg)instead of compound 30a, compound 31b (38 mg) was obtained.

Compound 31a:

TLC: Rf 0.40 (methylene chloride:methanol=4:1);

NMR (CDCl₃): δ 1.51-1.71 (m, 3H), 1.73 (s, 3H), 1.84-2.60 (m, 11H),3.22-3.49 (m, 2H), 3.59-3.79 (m, 1H), 4.64-4.76 (m, 2H), 5.53 (dd,J=15.20, 7.80 Hz, 1H), 5.66 (ddd, J=15.20, 7.80, 6.00 Hz, 1H), 8.10 (s,1H).

Compound 31b:

TLC: Rf 0.40 (methylene chloride:methanol=4:1);

NMR (CDCl₃): δ 1.50-1.82 (m, 6H), 1.86-2.59 (m, 11H), 3.26-3.47 (m, 2H),3.58-3.78 (m, 1H), 4.71 (d, J=5.12 Hz, 2H), 5.53 (dd, J=15.23, 7.80 Hz,1H), 5.67 (dt, J=15.23, 6.72, 6.59 Hz, 1H), 8.10 (s, 1H).

Example 31 (1)˜Example 31 (5)

By the same procedure as described in Example 26→Example 27→Example28→Example 29→Example 30→Example 31 using the corresponding compoundsinstead of compound 5, the following compounds were obtained.

Example 31 (1)2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclobutyl-4-hydroxy-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 31-1)

TLC: Rf 0.46 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.30-2.59 (m, 21H), 3.24-3.45 (m, 2H), 3.56-3.75 (m, 1H),5.54 (dd, J=15.00, 7.50 Hz, 1H), 5.59-5.74 (m, 1H), 8.11 (s, 1H).

Example 31 (2)2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-8-methyl-1,8-nonadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 31-2)

TLC: Rf 0.56 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.38-1.55 (m, 4H), 1.54-2.35 (m, 13H), 2.36-2.62 (m, 2H),3.23-3.51 (m, 2H), 3.56-3.88 (m, 3H), 4.69 (dd, J=10.06, 0.73 Hz, 2H),5.54 (dd, J=15.18, 7.86 Hz, 1H), 5.60-5.78 (m, 1H), 8.10 (s, 1H).

Example 31 (3)2-[(2-{(1R,5R)-2-oxo-5-[(1E,4S)-7,7,7-trifluoro-4-hydroxy-1-hepten-1-yl]cyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 31-3)

TLC: Rf 0.46 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.53-1.85 (m, 3H), 1.84-2.60 (m, 11H), 2.61-3.85 (m, 2H),3.22-3.50 (m, 2H), 3.63-3.81 (m, 1H), 5.32-5.80 (m, 2H), 8.10 (s, 1H).

Example 31 (4)2-[(2-{(1R,2R)-2-[(1E,4S,7S)-4-hydroxy-7-methyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 31-4)

TLC: Rf 0.46 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 0.79-0.94 (m, 6H), 1.01-1.76 (m, 8H), 1.83-2.61 (m, 9H),3.22-3.45 (m, 2H), 3.57-3.72 (m, 1H), 5.54 (dd, J=15.00, 7.68 Hz, 1H),5.60-5.76 (m, 1H), 8.11 (s, 1H).

Example 31 (5)2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-7-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)sulfonyl]-1,3-thiazole-4-carboxylicacid (compound 31-5)

TLC: Rf 0.44 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.55-1.72 (m, 3H), 1.74 (s, 3H), 1.88-2.50 (m, 11H),3.52-3.89 (m, 3H), 4.72 (d, J=5.49 Hz, 2H), 5.52 (dd, J=14.82, 8.04 Hz,1H), 5.59-5.74 (m, 1H), 8.58 (s, 1H).

Example 322-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 32)

By the same procedure as described in Example 9→Example 10→Example11→Example 15→Example 16→Example 17 using5-({3-methyl-3-[(trimethylsilyl)oxy]-6-heptan-1-yl}sulfonyl)-1-phenyl-1H-tetrazoleinstead of compound 5, the title compound having the following physicaldata was obtained.

TLC: Rf 0.60 (ethyl acetate:methanol:acetic acid=15:1:1);

NMR (CDCl₃): δ 1.18 (s, 3H), 1.46-1.73 (m, 3H), 1.84-2.29 (m, 9H),2.30-2.58 (m, 2H), 3.35 (t, J=7.50 Hz, 2H), 4.89-5.09 (m, 2H), 5.51 (dd,J=15.75, 6.96 Hz, 1H), 5.59-5.92 (m, 2H), 8.09 (s, 1H).

Example 33(10R,12E,13aR)-10-(1-hexyn-1-yl)-10-methyl-1,2,11,13a,14,15-hexahydro-8H-7,4-(azeno)pyrrolo[1,2-j][1,5,7,10]oxadithiazacyclopentadecine-8,16(10H)-dione(compound 33)

To a solution of compound 24-3 (50 mg) and 4-(dimethylamino)pyridine (70mg) in toluene (11.5 mL) was added dropwise 2,4,6-trichlorobenzoylchloride (0.036 mL) under a reflux condition. An hour later, thereaction solution was cooled to room temperature, and thereto was added1N hydrochloric acid. The organic layer was washed with an aqueoussaturated solution of sodium bicarbonate and brine, and dried overanhydrous magnesium sulfate. The reaction solution was filtered throughCelite (trade name), and concentrated. The obtained residue was purifiedby column chromatography on silica gel (n-hexane:ethylacetate=60:40→45:55) to give the title compound (18.6 mg) having thefollowing physical data.

TLC: Rf 0.36 (n-hexane:ethyl acetate=2:3);

NMR (CDCl₃): δ 0.90 (t, J=7.14 Hz, 3H), 1.31-1.59 (m, 4H), 1.62-1.79 (m,1H), 1.81-1.87 (m, 3H), 2.09-2.58 (m, 6H), 2.92 (dd, J=14.27, 11.16 Hz,1H), 3.17-3.33 (m, 1H), 3.32-3.48 (m, 1H), 3.60-3.87 (m, 2H), 4.04-4.18(m, 1H), 5.58 (ddd, J=14.91, 8.87, 1.65 Hz, 1H), 5.81 (ddd, J=14.91,11.16, 3.29 Hz, 1H), 7.97 (s, 1H).

Example 342-[(2-{(2R)-2-[(1E,4R)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 34)

To a solution of compound 33 (18.6 mg) in a solution of ethanol (0.44mL)/dimethoxyethane (0.44 mL) was added dropwise 2N sodium hydroxide(0.067 mL), and the mixture was stirred overnight. To the reactionsolution was added 1N hydrochloric acid (1.0 mL), and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over anhydrous magnesium sulfate, and concentrated togive the title compound (19.4 mg) having the following physical data wasobtained.

TLC: Rf 0.45 (ethyl acetate:methanol:acetic acid=8:1:1);

NMR (CDCl₃): δ 0.90 (t, J=7.14 Hz, 3H), 1.12-1.57 (m, 7H), 1.64-1.88 (m,1H), 2.01-2.65 (m, 7H), 3.00-4.93 (m, 2H), 3.23-3.44 (m, 2H), 3.44-3.60(m, 1H), 3.74-3.96 (m, 1H), 4.05-4.23 (m, 1H), 5.42 (dd, J=15.19, 8.78Hz, 1H), 5.64-6.10 (m, 1H), 8.08 (s, 1H).

Example 34 (1), Example 34 (2)

By the same procedure as described in Example 33→Example 34 usingcompound 24-2 or2-[(2-{(2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid instead of compound 24-3, the following compounds were obtained.

Example 34 (1)2-[(2-{(2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 34-1)

TLC: Rf 0.28 (ethyl acetate:methanol:acetic acid=8:1:1);

NMR (CDCl₃): δ 0.87 (t, J=6.59 Hz, 6H), 1.06-1.31 (m, 5H), 1.33-1.55 (m,3H), 1.65-1.88 (m, 1H), 2.13-2.59 (m, 5H), 3.15-3.61 (m, 3H), 3.71-3.95(m, 1H), 4.02-4.26 (m, 1H), 4.32-6.22 (m, 2H), 5.37 (dd, J=15.19, 8.97Hz, 1H), 5.71-6.01 (m, 1H), 8.09 (s, 1H).

Example 34 (2)2-[(2-{(2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid (compound 34-2)

TLC: Rf 0.44 (ethyl acetate:methanol:acetic acid=5:1:1);

NMR (CDCl₃): δ 1.20 (s, 3H), 1.52-1.68 (m, 2H), 1.67-1.87 (m, 4H),1.98-2.16 (m, 2H), 2.15-2.57 (m, 5H), 2.66-4.90 (m, 2H), 3.18-3.43 (m,2H), 3.42-3.59 (m, 1H), 3.72-3.91 (m, 1H), 4.02-4.25 (m, 1H), 4.51-4.89(m, 2H), 5.38 (dd, J=15.28, 9.06 Hz, 1H), 5.87 (dt, J=15.28, 7.50, 7.32Hz, 1H), 8.09.

Biological Example

It was proved for example by the following experiments that an EP2agonist which may have an EP3 agonistic effect has a nerve regenerativeand/or protective activity.

The whole operation was carried out by using conventionally used methodsbased on the fundamental biological techniques. Additionally, for thepurpose of evaluating the compounds of the present invention,improvement of measuring accuracy and/or improvement of measuringsensitivity was added to in the following manner. The following showsthe experimental methods in detail.

(1) Measurement of EP2 Agonist and EP3 Agonist Activities

(1-1) Measurement of EP2 Agonist Activity (Measurement of IntracellularCyclic AMP (cAMP) Concentration (cAMP Assay))

Cell Culture

A rat EP2 receptor forced expression cell (rEP2-CHO cell) was incubatedin an incubator (5% CO₂) of 37° C. using Minimum Essential Medium Eagle(Sigma, M4526) to which 10% fetal bovine serum (FBS, JRH) and 1/100total volume of Penicillin Streptomycin Glutamine (GIBCO, 10378-016) hadbeen added. The cells which reached confluent were exfoliated usingtrypsin and suspended in a medium (MEM medium containing 10% FBS) to adensity of 2.0×10⁵ cells per ml. The thus prepared suspension was seededinto a 24 well plate to be 1.0×10⁵ cells per well portions and incubatedfor 48 hours.

Compound Treatment

After the culturing, each well of the plate was washed with MinimumEssential Medium Alpha Medium (α-MEM medium; GIBCO, 41061-029 (500 μL))and incubated for 10 minutes in an incubator (5% CO₂) of 37° C. byadding the α-MEM medium (500 μL) supplemented with diclofenac sodium (2μmol/L). Thereafter, the medium was discarded. Assay buffer (1% bovineserum albumin (BSA)-containing α-MEM medium supplemented with diclofenacsodium (2 μmol/L) and isobutyl methyl xanthine (IBMX, 1 mmol/L)) wasadded to each well in the plate in 450 μL/well portions, and theculturing was again carried out for 10 minutes. The compound treatmentwas carried out by adding 50 μL of a compound solution (5% DMSO) whichwas prepared using the assay buffer to a 10 times concentration of itsfinal concentration to each well of the plate and carrying out theculturing in an incubator (5% CO₂) at 37° C. for 10 minutes. After thecompound treatment, the reaction was stopped by adding 10%trichloroacetic acid (500 μL) to each well, and the sample was frozen at−80° C.

Measurement of cAMP Concentration

The frozen sample was thawed and transferred to a micro centrifugationtube to be centrifuged (15,000 rpm, 4° C., 3 minutes). Then thesupernatant (500 μL) was collected. To the supernatant, 500 μL of anextraction solution (chloroform solution containing tri-n-octylamine(0.5 mol/L)) was added and again centrifuged (15,000 rpm, 4° C., 3minutes). Then the upper layer (100 μL) was collected. Using the upperlayer as a sample, cAMP concentration was measured by a cAMP EIA system(cAMP Enzyme Immunoassay System, Amersham Biosciences).

Data Analysis

Activity strengths of respective compounds were compared by calculatingtheir EC₅₀ values. The EC₅₀ value was calculated by regarding changedamount of the cAMP concentration when PGE₂ (1 μmol/l) was added insteadof each compound as the maximum changed amount, and defining the valuewhich gives half of the changed amount as the concentration of eachcompound.

(1-2) Measurement of EP3 Agonist Activity (Intracellular CalciumConcentration Real Time Imaging (Ca²⁺ Assay)) Cell Culture

A rat EP3 receptor forced expression cell (rEP3-CHO cell) was incubatedin an incubator (5% CO₂) of 37° C. using Minimum Essential Medium Eagle(Sigma, M4526) to which 10% fetal bovine serum (FBS, JRH) and 1/100 oftotal volume of Penicillin Streptomycin Glutamine (GIBCO, 10378-016) hadbeen added. The cells which reached confluent were exfoliated usingtrypsin and suspended in a medium (MEM medium containing 10% FBS) to adensity of 1.0×10⁵ cells per ml. The thus prepared suspension was seededinto a FDSS-3000 (Hamamatsu Photonics)-corresponding 96 well plate in100 μL per well portions and incubated for 48 hours.

Measurement of Intracellular Calcium Concentration

After the incubation, the culture fluid was removed from each well ofthe plate and a Fura2 loading buffer (10% FBS-containing MEM mediumsupplemented with Fura2-AM (5 μmol/L), HEPES (10 mmol/L), probenecid(2.5 mmol/L) and indometacin (20 μmol/L)) was added thereto, followed byincubating in an incubator (5% CO₂) of 37° C. Thereafter, the Fura2loading buffer was removed. Each well was washed twice (100 μL×2) usinga wash buffer (0.1% BSA-containing Hanks-HEPES buffer supplemented withprobenecid (2.5 mmol/l) and indometacin (2 μmol/L)), 120 μL of an assaybuffer (1% BSA-containing Hanks-HEPES buffer supplemented withprobenecid (2.5 mmol/l) and indometacin (2 μmol/L)), and then it wasincubated in an incubator (5% CO₂) of 37° C. for 30 minutes. The platewas further allowed to stand still for 15 minutes at room temperature ina dark and subjected to an intracellular calcium concentration real timeimaging using FDSS-3000. Compound solution (5% DMSO) prepared to a 5times concentration of its final concentration. After pre-incubation ofthe plate for 5.5 minutes, 30 μL thereof was directly added to eachwell. Measurement of the fluorescence intensity was continuously carriedout for 3 minutes after addition of the compound.

Data Analysis

Activity intensity of each compound was compared by calculating theirEC₅₀ values. The EC₅₀ value was calculated by regarding mean of thechanged amount of calcium concentration when PGE₂ (100 nmol/L) was addedinstead of each compound as the maximum changed amount, and defining thevalue which gives half of the changed amount as the concentration ofeach compound. In this connection, the changed amount of calciumconcentration was calculated by subtracting a ratio of “fluorescenceintensity at 500 nm by an excitation light of 380 nm” to “fluorescenceintensity at 500 nm by an excitation light of 340 nm” (Ex340/Ex380)during 10 to 20 seconds before the addition of the compound or mediumfrom the peak value of Ex340/Ex380 during 3 minutes after the additionof the compound or medium.

Results

EP2 agonist and EP 3 agonist activities of compounds represented by theformula (I) were measured using the above method. For example, EC₅₀values of the EP2 agonist and EP 3 agonist of the compound A were 0.016μM and 0.099 μM, respectively, while EC₅₀ values of the EP2 agonist andEP 3 agonist of the compound 17 were 0.011 μM and 0.031 μM,respectively.

(2) Measurement of Cauda Equina Nerve Repair Acceleration Activity

A rat cauda equina nerve compression gait disturbance model was preparedby the method of Takenobu et al. (J. Neurosci. Methods, 104 (2),191-198, 2002). Namely, a rat was anesthetized with pentobarbital sodiumand, after shaving its dorsal region, fixed at abdominal position. Afterdisinfection of the dorsal region with chlorhexidine gluconate (5%hibitane liquid; Sumitomo Pharmaceuticals), the waist was median-incisedto expose the spinal column. After excision of the fifth lumbar gemmule,a silicon rubber of 1×4×1.25 mm (height×length×width) was inserted intothe fourth lumbar and sixth lumbar spinal canals from a small hole onthe vertebral arch bored by a mini drill. For the purpose of avoidinginfections, benzylpenicillin potassium (Crystalline Penicillin GPotassium Meiji; Meiji Seika Kaisha, Ltd.) was added dropwise to theincised part and intramuscularly injected into the thigh parts. Themuscle and skin of the incised part were stitched with a surgicalsuture, and Iodine Tincture was applied to the stitched part. Animals ofthe sham operation group were prepared in accordance with theaforementioned method, but the insertion of silicon rubber was notcarried out. After the operation, the compound A as a compoundrepresented by the formula (I) and physiological saline were subjectedto intravenous continuous administration (2 hours×twice/day, 2 weeks). Arat spinal cord specimen after completion of the administration of asubstance to be tested was subjected to decalcification by an ionexchange resin method, and the cauda equina nerve of the fifth lumbarpart was extracted to prepare a paraffin section of about 4 μm inthickness to carry out pathologic and histological inspection afterstaining with hematoxylin & eosin. Nerve fascicles in the section wereclassified in accordance with the following condition classification tocalculate appearance rate of regeneration nerve fascicles.

Condition Description Regeneration Fascicles at the stage of Schwanntube formation. Phagocytosis Fascicles at the stage of phagocytosis andelimination and elimination of debris by Schwann cells and macrophagesDegeneration Fascicles at the stage of axonal degeneration Normal Normalfascicles

As a result, the compound A administration group showed significantlyhigh appearance rate of regeneration nerve fascicles in comparison withthe physiological saline administration group. Based on the above, itwas suggested that the agent of the present invention has a nerve tissueregeneration activity.

(3) The Measurement of the Cauda Equina Blood Flow and the BloodPressure

1.5 g/kg of urethane was administered intraperitoneally to the rat to beanesthetized, and the catheter (for measurement of blood pressure andventricular rate) was placed in left carotid artery in supine position.The rat was reversed to prone position and the lumbar part was incisedin the median line. The laminectomy was given to the fifth lumbarvertebra and the spinal cord (cauda equina) was exposed. The caudaequina blood flow was measured by the laser-Doppler flowmetry (OMEGAFLDFLO-NI and ADVANCE LASER FLOWMETER ALF21N, OMEGA WAVE Inc.) through anoncontact probe (ST-N type, OMEGA WAVE Inc.) and recorded withLINEARCORDER (Graphtech). The systemic blood pressure and theventricular rate were measured from a left carotid artery with amplifierfor the pressure measurement (GOULD) through a pressure transducer andrecorded with LINEARCORDER (Graphtech). After confirming each parameterof blood pressure, ventricular rate and blood flow was stabilized, thetest compound was administrated by continuous infusion through thewinged needle placed in caudal vein for 30 minutes. It observed until 30minutes after the administration and the increase rate of the caudaequina blood flow was calculated.

The increase rate of the cauda equina blood flow (%)=(B−A)/A×100A: the cauda equina blood flow before the administration of the testcompoundB: the cauda equina blood flow after the administration of the testcompound

As a result, the compounds which are represented by formula (I)increased the cauda equina blood flow although they had weak bloodpressure-lowering effect. For instance, Compound 17 of the compoundswhich are represented by formula (I) increased 33% of the cauda equinablood flow, while it decreased only 5 mmHg of the blood pressure.

Formulation Example Formulation Example 1

Compound 17 (5.0 g), carboxymethyl cellulose calcium (20 g), magnesiumstearate (10 g) and microcrystalline cellulose (920 g) were admixed in aconventional method and punched out to obtain 10,000 tablets eachcontaining 0.5 mg of the active ingredient.

Formulation Example 2

Compound 17 (2.0 g), mannitol (500 g) and distilled water (10 L) wereadmixed in a conventional method, and the solution was sterilized in aconventional method, placed at 1 mL into vials and freeze-dried in aconventional method to thereby obtain 10,000 vials each containing 0.2mg of the active ingredient.

INDUSTRIAL APPLICABILITY

An EP2 agonist which may have an EP3 agonistic effect has an effect ofregenerating and/or protecting nerves, and is therefore useful as atherapy such as a disease of the peripheral nervous system. An EP2agonist having an EP3 agonistic effect is useful as a safe and effectiveagent for the regeneration and/or protection of nerves which has littleinfluence on the circulatory system.

1. An agent for regeneration and/or protection of nerves comprising anEP2 agonist which may have an EP3 agonistic effect.
 2. The agent for theregeneration and/or protection of nerves according to claim 1,comprising an EP2 agonist having an EP3 agonistic effect.
 3. The agentaccording to claim 2, wherein the EP2 agonist having an EP3 agonisticeffect is a compound represented by formula (I):

wherein ring A is a 5 or 6-membered ring which may comprise 1 to 3hetero atom(s) selected from nitrogen, oxygen and sulfur in addition toX and Y, and furthermore may have a substituent(s), X and Y are eachindependently nitrogen or carbon, D is hydrocarbon which may have asubstituent(s), E is a bond, oxygen or optionally oxidized sulfur, G isa bond, hydrocarbon which may have a substituent(s) or hetero ring whichmay have a substituent(s), J is an acidic group which may be protected,W is hydrocarbon which may have a substituent(s), a salt thereof, anN-oxide thereof, an S-oxide thereof, a solvate thereof or a prodrugthereof, or a cyclodextrin clathrate thereof.
 4. The agent according toclaim 3, wherein the compound represented by formula (I) is a compoundrepresented by formula (I-1):

wherein ring A¹ is 5 or 6 membered ring which may comprise 1 to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur in addition to X andY, and may have more substituent(s), E¹ is oxygen or optionally oxidizedsulfur, R is hydrogen or C1-8 aliphatic hydrocarbon group, and the othersymbols have the same meanings as those described in the claim
 3. 5. Theagent according to claim 4, wherein the compound represented by formula(I-1) is a compound represented by (I-5):

wherein R¹ is hydrogen or C1-4 aliphatic hydrocarbon group, R² ishydrocarbon group which may have a substituent(s),

is β-configuration, and the other symbols have the same meanings asthose described in the claim
 4. 6. A medicament combined an EP2 agonisthaving an EP3 agonistic effect, with one or more selected from an EP2agonist and an EP3 agonist.
 7. The agent according to claim 1, whereinthe regeneration and/or protection of nerves is a prevention and/or atreatment for a disease of the peripheral nervous system.
 8. Amedicament comprising an EP2 agonist which may have an EP3 agonisticeffect, and one or more species selected from prostaglandins,prostaglandin derivatives, nonsteroidal anti-inflammatory drugs,vitamins, muscle relaxants, antidepressants, nitric oxide synthaseinhibitors, aldose reductase inhibitors, poly ADP-ribose polymeraseinhibitors, excitatory amino acid receptor antagonists, radicalscavengers, astrocyte modulators, phosphodiesterase inhibitor andimmunosuppressive agent in combination.
 9. A method for the regenerationand/or protection of nerves, which comprises administering to a mammalan effective amount of an EP2 agonist which may have an EP3 agonisticeffect.
 10. A use of an EP2 agonist which may have an EP3 agonisticeffect, for the manufacture of an agent for regeneration and/orprotection of nerves.
 11. A compound represented by formula (I-2):

wherein ring A² is a 5 or 6-membered ring which may comprise 1 to 3hetero atom(s) selected from nitrogen, oxygen and sulfur, and may havemore substituent(s), and the other symbols have the same meanings asthose described in the claim 4, excluding2-[(2-{(1R,2R)-2-[(1E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylicacid,2-[(2-{(1R,2R)-2-[(1E,3R)-3-hydroxy-4,4-dimethyl-1-octenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylicacid,2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1-nonenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylicacid,2-[(2-{(1R,2R)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxocyclopentyl}ethyl)sulfanyl]-1,3-thiazole-4-carboxylicacid and2-[(2-{(1R,2R)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxocyclopentyl}ethyl)sulfonyl]-1,3-thiazole-4-carboxylicacid, a salt thereof, an N-oxide thereof, an S-oxide thereof, a solvatethereof or a prodrug thereof, or a cyclodextrin clathrate thereof. 12.The compound according to claim 11, which is represented by formula(I-3):

wherein

is α-configuration, and the other symbols have the same meanings asthose described in the claim 4 and claim
 5. 13. The compound accordingto claim 12, wherein R¹ is hydrogen or C1-4 alkyl group, R² is C1-8aliphatic hydrocarbon group which may have a substituent(s), or (C3-8cycloalkyl)-(C1-4 aliphatic hydrocarbon) group which may have asubstituent(s).
 14. The compound according to claim 11, which isselected from2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclohexyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,8-dimethyl-1,7-nonadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4-methyl-1-nonen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,2-[(2-{(1R,2R)-2-[(1E)-4-hydroxy-4-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4,8-dimethyl-1-nonen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclobutyl-4-hydroxy-4-methyl-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylis acid,2-[(2-{(1R,2R)-2-[(1E,4R)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,2-[(2-{(1R,2R)-2-[(1E,4S)-4-hydroxy-7-methyl-1,7-octadien-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid and2-[(2-{(1R,2R)-2-[(1E,4S)-6-cyclobutyl-4-hydroxy-1-hexen-1-yl]-5-oxocyclopentyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid. 15.2-[(2-{(2R)-2-[(1E)-5-cyclohexyl-4-hydroxy-4-methyl-1-pentenyl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,2-[(2-{(2R)-2-[(1E)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,2-[(2-{(2R)-2-[(1E)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,2-[(2-{(2R)-2-[(1E,4R)-4-hydroxy-4-methyl-1-decen-5-yn-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid,2-[(2-{(2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid or2-[(2-{(2R)-2-[(1E,4S)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylicacid, a salt thereof, an N-oxide thereof, an S-oxide thereof, a solvatethereof or a prodrug thereof, or a cyclodextrin clathrate thereof. 16.An agent for the regeneration and/or protection of nerves, or an agentto increase cauda equina blood flow comprising the compound which isrepresented by formula (I-2) or the compound according to claim 15, thesalt thereof, the N-oxide thereof, the S-oxide thereof, the solvatethereof or the prodrug thereof, or the cyclodextrin clathrate thereof.17. The agent according to claim 16, which is a preventive and/or atherapeutic agent for spinal canal stenosis and/or cervical vertebrasymptom.